Dermatopathology Updates on

Me la no cytic L esio n s
Wang L. Cheung, MD, PhDa,*, Bruce R. Smoller, MDb

KEYWORDS

Melanocytes
Nevi
Melanoma
Special site

KEY POINTS

Special site nevi such as those on the breast and genitalia tend to have more cytologic and archi-
tectural atypia but can be considered benign changes.

The histopathology of melanocytic proliferations during pregnancy does not appear to differ
significantly.

Atypical dermal melanocytic proliferations are difficult to diagnose and tend to have a better
outcome after adequate treatment.

Additional histopathologic studies along with longer clinical follow-up are required to determine if
atypical dermal melanocytic proliferations and special site nevi will behave as low grade malignant
neoplasms or benign neoplasms.

This article examines some of the recent studies on
interesting melanocytic lesions, such as site-
specific nevi, “Spark’s” nevi, nevi during pregnancy,
and atypical dermal melanocytic proliferation,
including pigmented epithelioid melanocytoma,
proliferating nodules, and atypical Spitzoid tumor. In
general, the studies with both histopathologic find-
ings and clinical outcome are most informative, allow-
ing dermatopathologists and dermatologists to
identify the histologic features that are most helpful.
Although newer immunohistochemical and molecular
tests are available, they currently confirm the hema-
toxylin and eosin (H&E) findings and remain ancillary
studies. More histopathologic studies with clinical
follow-up are still needed to help understand the
behavior of some melanocytic lesions.
SITE-SPECIFIC NEVI (DYSPLASTIC NEVI OR
NOT?)
Normal skin biopsies from different anatomic
locations from 97 patients in Australia were exam-
ined for the distribution of melanocytes using an
immunohistochemical stain for tyrosinase-related
protein 1.1 This study showed that overall melano-
cyte density decreases with age, and the density is
highest on the back, shoulder, and limbs. In addi-
tion, patients with more nevi had a higher density
of melanocytes. Hair color, eye color, and freckling
did not have an impact on the density of melano-
cytes. Another study of 506 Australian children
showed that the highest number of nevi were on
the arms, neck, and face. Girls had more nevi on
the lower leg and thigh than boys.2 These simple
and eloquent studies show that the density of mela-
nocytes and nevi differ, suggesting that the biology
of melanocytes from different locations and
genders may vary. Reasoning would follow that
melanocytic proliferations from different locations
and genders also will probably be different.
Hosler and colleagues3 recently wrote an excel-
lent review on nevi with site-related atypia., cate-
gorizing them into 4 groups: acral, genital,
special-site, and conjunctival. And they review on
nevi with site-related atypia, the special-site cate-
gory included breast, flexural, scalp, and auricular
derm.theclinics.com

The authors have nothing to disclose.

a
Department of Pathology, Orlando Health, 1414 Kuhl Avenue, Orlando, FL 32806, USA; b United States and
Canadian Academy of Pathologist, 3643 Walton Way Extension, Augusta, GA 30909, USA
* Corresponding author.
E-mail address: wang.cheung@orlandohealth.com

Dermatol Clin 30 (2012) 617–622

http://dx.doi.org/10.1016/j.det.2012.06.014
0733-8635/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
618 Cheung & Smoller

sites.4 These special-site nevi can have more cyto-
logic atypia and architectural disorder than other
sites (Fig. 1). For example, 101 breast nevi showed
more dermal fibroplasia, cytologic atypia, and in-
traepidermal melanocytes compared with 97 other
nevi.5 Similar studies from other special sites have
also been reported. However, these studies do not
address whether these atypical nevi really repre-
sent completely benign nevi or whether dysplastic
nevi occur more frequently at these sites. Recogni-
tion is important to ensure that melanoma is not
overdiagnosed. However, in some instances,
whether atypia is attributed to site-specific
changes is not straightforward, and some derma-
topathologists might still recommended complete
conservative removal.6
Atypical genital nevi, regarded as nevi of a special
site, have unique histopathologic findings. These
nevi, especially in premenopausal women, consist
of large and irregular junctional nests with focal
single cells in a lentiginous growth pattern and in
the spinous layer of the epidermis and adnexal
structures.7 The melanocytes can also have mild
to severe cytologic atypia but are uniform. Usually
superficial dermal fibrosis is present, likely from
prior trauma. The dermal component can be very
dense, containing nests and many single melano-
cytes, again with cytologic atypia. Focally, an
increase in mitoses can be seen, but maturation is
present and no deep dermal or atypical mitoses
are identified (Fig. 2). Although limited data are
available, atypical genital nevi may recur when
incompletely excised.7 The most important distinc-
tion is vulvar melanoma, but usually these are larger
clinically and present in older women with histo-
pathologic features of frank melanoma.
Recently, the histopathologic features of
dysplastic nevi on the lower leg were further exam-
ined.8 The authors examined 62 dysplastic nevi of
the lower leg from women and men and compared
them with 20 dysplastic nevi from the back and 20
superficial spreading melanoma of the lower leg.
The women showed more pagetoid spread, more
cytologic atypia, and larger melanocytes in
dysplastic nevi. The authors also noted that
lesions larger than 4 mm are more likely to be
diagnosed as melanoma.8 These types of studies
are informative but again do not address whether
these changes are really benign or precursors to
a malignant process, and do not address whe-
ther these lesions from the lower leg represent
distinct site-specific change of benign nevi or are
dysplastic nevi.
Whether dysplastic nevi are a precursor to mela-
noma is not certain, but presence of multiple nevi
(especially dysplastic) definitely is a risk factor for
melanoma. Many studies have found that mela-
noma is strongly associated with total number of
nevi, such that the relative risk is 6.89 for patients
with more than 100 nevi versus those with fewer
than 15 nevi.9 The relative risk is even higher for
atypical nevi. One study from Queensland,
Australia showed that people with low numbers of
nevi who are exposed to frequent sunlight tend to
develop head and neck melanomas, whereas
people with many nevi who are exposed to rare
sunlight tend to develop truncal melanomas.10 A
more recent study showed a site-specific correla-
tion of number of nevi to risk of melanoma on the
back, but not on other locations.11 In other words,
increasing numbers of nevi in a particular location
might not increase the risk of developing melanoma
in that same location, rather the general increase in
risk is seen throughout the body. These clinical
studies might support that the special-site nevi as
described earlier are benign nevi with distinct atyp-
ical features. By themselves, these special-site nevi
probably do not increase the risk of melanoma in

Fig. 1. A melanocytic lesion from the breast of a 25-year-old woman. The low-power histopathologic examina-
tion shows architectural disorder (ie, lamellar fibroplasia, bridging of the rete ridges, irregular and enlarged
nests, and scattered single melanocytes in the epidermis). The dermal component contains smaller melanocytes
(A). The higher-power view shows more architectural disorder and moderate cytologic atypia (B). Even though
cytologically atypical cells are present, many of the junctional melanocytes appear similar.
 Melanocytic Lesions Updates 619

Fig. 2. A melanocytic lesion from the vulva of a 14-year-old girl. The low-power view shows a large melanocytic
lesion with pedunculation. Enlarged nests of melanocytes are present in the epidermis and superficial dermis.
However, the cells in the dermis seem to mature even in this low-power view (A). With higher magnification,
irregular-shaped nests are seen, predominately at the dermoepidermal junction. In the dermis, many melanocytes
appear as single cells and in nests. Although cytologic atypia is present, it is uniform (B). Of course, more importantly,
the dermal melanocytes do mature and the proliferation index remains low.

that location. The only exception might be the
back.11 This finding also might mean that the atypia
seen in nevi from the back probably should not be
considered as changes attributed to a special site.
“SPARK’S” NEVI
Recently, the name Spark’s nevi was proposed for
nevi with features of Spitz and Clark’s dysplastic
nevi.12 Histologically, the authors reported 27
cases having epithelioid and spindle cells at the
dermoepidermal junction and in the papillary
dermis. These lesions were well circumscribed,
symmetric, and had melanocytes of similar size,
shape, and small diameter. Furthermore, most
(23/27) of these lesions had Kamino bodies. Clini-
cally, these patients were predominately young
(mean age, 33 years) with a female predominance
(63%). These nevi were most common on the trunk
or lower extremity (20/27). Toussaint and Kamino13
also reported lesions similar to these, which they
called “dysplastic Spitz’s nevus.” They described
67 of these cases. Similarly, these lesions were
usually seen in younger patients (mean age, 34.7
years) and located on the lower extremity (44%).
The recent study by Ko and colleagues12 included
an average of 10 years’ follow-up in 12 patients,
showing no recurrences or metastasis in any of
these patients.
PREGNANCY EFFECT ON MELANOCYTIC
PROLIFERATION
During pregnancy, hyperpigmentation of the
areola, axilla, and other locations is noted. In addi-
tion, darker melanocytic nevi have also been
documented during pregnancy. One objective
study that followed melanocytic nevi in 22 patients
using photographs and, in some cases, biopsy
showed no significant difference during the preg-
nancy.14 Two earlier studies also found little or
no histologic differences in nevi of pregnant
women versus control women.15,16
A recent study examining in more detail the histo-
logic features of melanocytic nevi in pregnancy
compared 16 melanocytic nevi from pregnant
women with 15 melanocytic nevi from nonpregnant
women matched for location and age.17 The inves-
tigators found an increased number of epithelioid
melanocytes in the superficial dermis (Fig. 3A),
termed superficial micronodules of pregnancy.
The pregnancy nevi were also more likely to have
dermal mitotic figures (62.5% vs 13.3%) and higher
mitotic rate (1.44 vs 0.2 mitoses per mm2) than non–
pregnancy-related nevi (see Fig. 3B). However,
despite a trend, the difference in Ki-67 staining
was not statistically significant, suggesting that
the overall proliferation rate may not differ between
the groups (see Fig. 3C, D). Although Ki-67 levels
might become statistically significant with more
cases, the mitotic rate determined by mitoses
counted and Ki-67 index may be slightly different.
After all, Ki-67 immunostain will highlight cells that
are entering mitoses before any evidence is detect-
able on H&E-stained sections. Another unexpected
finding was that the multinucleated melanocytes
common in benign nevi were not noted in preg-
nancy nevi. The relationship of these findings to
the hormonal state of pregnant women is not clear,
but at least some histologic difference seems to be
present between nevi from pregnant women and
those in controls.17
Spectrophotometric intracutaneous analyses
(SIAscopy) were performed in vivo on 381
620 Cheung & Smoller

Fig. 3. A melanocytic lesion from mons pubis of a pregnant 28-year-old woman. Superficial nodules composed of
slightly enlarged melanocytes are seen (A). Scattered mitoses are noted in the mid dermis (B). However, the Ki-67
still shows a low proliferation index with epidermis as control (C). An HMB-45 immunostain shows loss of staining
in the deeper dermal cells as an indicator of maturation, supporting that this is a benign lesion (D).

melanocytic nevi of pregnant women during early
pregnancy and before birth, and compared with
163 melanocytic nevi of nonpregnant women.18 SIA-
scopy uses different light sources to build a model of
where melanin pigment is located in the skin, and
supplements information that can be obtained with
only a dermatoscope. In the pregnant group, only
2.1% of nevi increased in size and 1.8% decreased
in size. Only one nevus increased in pigmentation,
whereas 3.7% of nevi decreased in pigmentation.
When compared with the nonpregnant group, no
statistical differences were found. These data
suggest that no significant changes are found in
nevi from women during pregnancy. Whether any
changes in nevi occur postdelivery would be inter-
esting to determine. Nonetheless, all of these studies
do not support the notion that melanocytic lesions
change during pregnancy. Therefore, a changing
melanocytic lesion in a pregnant woman should be
treated as though it is an atypical finding and
warrants biopsy.
ATYPICAL DERMAL MELANOCYTIC
PROLIFERATIONS
Atypical dermal melanocytic proliferations pose
a unique problem for dermatopathologists. When
marked cytologic atypia is seen along with higher
proliferation index, a dermal melanoma can be
diagnosed. However, in some dermal melanocytic
lesions, all of the criteria for dermal melanoma are
not met. These lesions create problems for the

pathologist because an accurate prognosis can-
not be given to the clinician. Furthermore, the
threshold and description of atypia can be subjec-
tive among different observers.
Proliferative Nodules in Congenital Nevi
One type of atypical dermal melanocytic prolifera-
tion is the proliferative nodule that can arise in
a congenital nevus. These nodules are clinically
soft and may regress, but some proliferative
nodules can have atypia. Differentiating them
from melanoma arising in a congenital nevus can
be challenging. According to the literature, the giant
congenital nevus can have a 6% to 14% lifetime
risk of developing melanoma.19 Therefore, atypical
proliferative nodules are important to distinguish
from melanoma and benign proliferative nodules.
Phadke and colleagues20 studied 18 benign and
25 atypical proliferative nodules using various
immunohistochemical proliferation markers and
molecular analyses. Atypical proliferative nodules
differed from the benign counterpart in that they
displayed sharp demarcation, expansile growth,
epidermal effacement, nuclear pleomorphism,
and increased mitoses. Molecular analysis showed
that more NRAS mutations are found in giant
congenital nevi and their proliferative nodules,
whereas medium or small congenital nevi and their
proliferative nodules have more BRAF mutations.
These mutational studies are interesting, but they
do not discriminate different types of proliferative
nodules. Both proliferation markers, Ki-67 and
pHH3, were noted to be higher in atypical versus
benign proliferative nodules. When comparing
atypical proliferative nodules with dermal
melanoma, the proliferation index is very similar,
suggesting that these atypical lesions are border-
line and perhaps have a potential to become
malignant.20
Pigmented Epithelioid Melanocytoma
Another example of an atypical dermal melano-
cytic proliferation is pigmented epithelioid melano-
cytoma (PEM). PEM was initially described in 2004
as a low-grade melanoma that metastasized to
lymph nodes but with better prognosis than
conventional melanoma.21 PEM includes epithe-
lioid blue nevus of Carney complex, which has
been found to have loss of cyclic adenosine 30 ,50
monophosphate (AMP)–dependent protein kinase
A regulatory subunit 1a (R1a).22 Histologically,
PEMs have distinct cytology, with epithelioid and
spindle cells that are heavily pigmented with
a very infiltrative pattern. To further understand
the malignant potential of these lesions, a more
recent study examined 26 cases of PEM with
Melanocytic Lesions Updates 621
median follow-up of 67 months (range, 39–216
months).23 The study showed that PEM behaves
much better than conventional melanoma. Even
though 8 of 18 patients who underwent sentinel
lymph node biopsy had positive results, all 26
patients (including those who were positive for
lymph node metastasis) are alive. Therefore, these
limited data support that PEM is a low-grade
tumor that can metastasize but does not cause
significant mortality.23
Other atypical dermal melanocytic proliferations
include nevoid borderline tumor, atypical Spitzoid
tumor, and atypical lesions arising from a deep
penetrating nevus. Magro and colleagues24 exam-
ined cases of each of these lesions and PEMs,
with an average follow-up of 4.2 years. They found
a total of 32 cases, and all but one patient was
alive and well. Many of these cases underwent
treatment similar to melanoma, with wide excision
and sentinel lymph node biopsy. The lymph node
positivity ranged from 14% to 57%, depending
on the category of atypical dermal melanocytic
proliferation (25% [1/4] nevoid borderline tumors,
35% [5/14] atypical Spitzoid tumors, 14% [1/7]
pigmented epithelioid melanocytomas, and 57%
[4/7] borderline tumors in deep penetrating nevi).
At first, this finding would support that, even
though these lesions have positive sentinel lymph
nodes, their biologic behavior is benign. However,
the only patient (a 36-year-old man) who died had
an atypical proliferation arising from a deep pene-
trating nevus. This lesion was diagnosed as
a benign lesion 2 years before metastasis.
Although it would be difficult to prove, the question
remains whether adequate treatment of these
lesions might explain the more benign behavior
of these lesions. In other words, the current treat-
ment for these atypical dermal melanocytic prolif-
erations is the same as for melanoma.
SUMMARY
In summary, special-site nevi, such as those on the
breast and genitalia, tend to have more cytologic
and architectural atypia, but these differences can
be considered benign. The histopathology of mela-
nocytic proliferations during pregnancy does not
seem to differ significantly. Atypical dermal mela-
nocytic proliferations are difficult to diagnose and
tend to have a better outcome after adequate treat-
ment. Additional histopathologic studies along with
longer clinical follow-up are required to determine if
atypical dermal melanocytic proliferation will
behave as a low-grade malignant neoplasm or
a benign neoplasm. These types of studies are
also needed for nevi of special (or different) sites
and other difficult melanocytic lesions.
622 Cheung & Smoller
REFERENCES
1. Whiteman DC, Parsons PG, Green AC. Determi-
nants of melanocyte density in adult human skin.
Arch Dermatol Res 1999;291:511–6.
2. Harrison SL, Buettner PG, MacLennan R. Body-site
distribution of melanocytic nevi in young Australian
Children. Arch Dermatol 1999;135:47–52.
3. Hosler GA, Moresi JM, Barrett TL. Nevi with site-
related atypia: a review of melanocytic nevi with
atypical features based on anatomic site. J Cutan
Pathol 2008;35:889–98.
4. Saad AG, Patel S, Mutasim DF. Melanocytic nevi of
the auricular region: histologic characteristics and
diagnostic difficulties. Arch Dermatol Res 2005;27:
111–5.
5. Ronglioletti F, Urso C, Batolo D, et al. Melanocytic
nevi of the breast: a histologic case-control study.
J Cutan Pathol 2004;31:137–40.
6. Elder D. Precursors to melanoma and their mimics:
nevi of special sites. Mod Pathol 2006;19:S4–20.
7. Gleason BC, Hirsh MS, Nucci MR, et al. Atypical
genital nevi: a clinicopathologic analysis of 56
cases. Am J Surg Pathol 2008;32:51–7.
8. Coras B, Landthaler M, Stolz W, et al. Dysplastic
melanocytic nevi of the lower leg: sex- and site-
specific histopathology. Am J Dermatopathol 2010;
32:599–602.
9. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis
of risk factors for cutaneous melanoma: I. common
and atypical naevi. Eur J Cancer 2005;41:28–44.
10. Whiteman DC, Watt P, Purdine DM, et al. Melano-
cytic nevi, solar keratoses, and divergent pathways
to cutaneous melanoma. J Natl Cancer Inst 2003;
95:806–11.
11. Randi G, Naldi L, Gallus AD, et al. Number of nevi at
a specific anatomical site and its relation to cuta-
neous malignant melanoma. J Invest Dermatol
2006;126:2106–10.
12. Ko CJ, McNiff JM, Glusac EJ. Melanocytic nevi with
features of Spitz nevi and Clark’s/dysplastic nevi
(“Spark’s” nevi). J Cutan Pathol 2009;36:1063–8.
13. Toussaint S, Kamino H. Dysplastic changes in
different types of melanocytic nevi. A unifying
concept. J Cutan Pathol 1999;26:84–90.
14. Grin CM, Rojas AI, Grants-Kels JM. Does
pregnancy alter melanocytic nevi? J Cutan Pathol
2001;28:389–92.
15. Foucar E, Bentley TJ, Laube DW, et al. A histo-
pathologic evaluation of nevocellular nevi in preg-
nancy. Arch Dermatol 1985;121:350–4.
16. Sanchez JL, Figueroa LD, Rodriguez E. Behavior of
melanocytic nevi during pregnancy. Am J Dermato-
pathol 1984;6(Suppl):89–91.
17. Chan MP, Chan MM, Tahan SR. Melanocytic nevi in
pregnancy: histologic features and Ki-67 prolifera-
tion index. J Cutan Pathol 2010;37:843–51.
18. Wyo Y, Synnerstad I, Fredrikson M, et al. Spectro-
photometric analysis of melanocytic naevi during
pregnancy. Acta Derm Venereol 2007;87:231–7.
19. Bittencourt FV, Marghoob AA, Kopf AW, et al. Large
congenital melanocytic nevi and the risk for devel-
opment of malignant melanoma and neurocutane-
ous melanocytosis. Pediatrics 2000;106:736–41.
20. Phadke PA, Rakheja D, Le LP, et al. Proliferative
nodules arising within congenital melanocytic nevi:
a histologic, immunohistochemical, and molecular
analyses of 43 cases. Am J Surg Pathol 2001;35:
656–69.
21. Zembowicz A, Carney JA, Mihm MC. Pigmented
epithelioid melanocytoma. Am J Surg Pathol 2004;
28:31–40.
22. Zembowicz A, Knoeepp SM, Bei T, et al. Loss of
expression of protein kinase a regulatory subunit
1alpha in pigmented epithelioid melanocytoma but
not in melanoma or other melanocytic lesions. Am
J Surg Pathol 2007;31:1764–75.
23. Mandal RV, Murali R, Lundquist KF, et al. Pigmented
epithelioid melanocytoma: favorable outcome after 5
year follow-up. Am J Surg Pathol 2009;33:1778–82.
24. Magro CM, Crowson AN, Mihm MC, et al. The
dermal-based borderline melanocytic tumor: a cate-
gorical approach. J Am Acad Dermatol 2010;62:
469–79.