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Oral melanocytic nevi: Report of two cases

with immunohistochemical elaboration of their
probable origin and maturation
Dip Du a, Venkatesh V. Kamath, Komali Rajkumar
Department of Oral and Maxillofacial Pathology, Dr. Syamala Reddy Dental College, Hospital and Research Centre, Bangalore,
Karnataka, India

A B S T R A C T
Oral melanocytic nevi are localized developmental tissue malformations of nevus cells in the oral mucosa. Relatively rare in occurrence
compared to their dermal counterparts, considerable debate exists in the literature related to their origin, development and maturation, and
their relationship to oral melanocytes.We report two cases of oral melanocytic nevi with classical clinical presentation. The histopathology was
consistent with the known patterns of oral melanocytic nevi. Special stains such as Masson Fontana, further substantiated the observation.
S-100 and HMB-45 were applied to immunohistochemically elaborate the cell population. Interestingly two distinct cell populations were
detected in the lesions. “Type A” cells in the center of the lesion were S-100 positive, indicating a neural origin and immaturity in development,
while peripheral “type B” cells stained positive with HMB-45, indicating melanocytic origin and mature development.

Key words: HMB-45, immunohistochemistry, oral melanocytic nevi, S-100

INTRODUCTION mucosa, and gingiva are the most commonly affected

Oral melanocytic nevi are probably derived from nevus
cells in the oral mucosa. The nevus cells, in turn, are
derived from neural crest cells that migrate to the
epithelium during development.[1]
Clinically, a pigmented nevus is an asymptomatic,
well-circumscribed, round or oval, flat or slightly
elevated spot or plaque, and of size usually ranging
between 0.1 cm and 3 cm. The color varies from brown
to blue, bluish gray to black. The hard palate, buccal
Corresponding Author: Dr. Venkatesh V. Kamath,
Department of Oral and Maxillofacial Pathology,
Dr. Syamala Reddy Dental College, Hospital and Research
Centre, Munnekolala, Marathahalli, Bangalore - 560 037,
Karnataka, India.
E-mail: kamathvv2003@yahoo.com
intraoral sites. They can be seen in persons of all ages
with the mean age group affected being 3rd-4th decade.
Women are affected more commonly than men.[2,3]
The stimulus for the development of oral nevi is
still unknown but it results in the proliferation of
melanocytes into the connective tissue. The cells
are round in shape and are present in clusters with
granular cytoplasm containing melanin pigment.
Multinucleated cell variants are also seen. The
classical interpapillary location (between the rete
ridges) is significant and is thought to be related to
the development of epithelium.[4]
Histologically, nevi are classified as intradermal/
intramucosal, junctional, and compound, based on
the pattern of proliferation of the nevus cells. In

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DOI: Cite this article as: Dutta D, Kamath VV, Rajkumar K. Oral melanocytic nevi:
10.4103/2349-6029.173413 Report of two cases with immunohistochemical elaboration of their probable
origin and maturation. Indian J Dermatopathol Diagn Dermatol 2015;2:29-33.

29 © 2015 Indian Journal of Dermatopathology and Diagnostic Dermatology | Published by Wolters Kluwer - Medknow
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Dutta, et al.: Oral melanocytic nevi: Report of two cases
the intramucosal variety, there is a proliferation of
nevus cells in the connective tissue with a band of
tissue separating the cells from the basal layer of
the epithelium. In the junctional variety, nevus cells
are present in the basal layer of the epithelium. The
compound nevi combine the characteristics of the
first two groups.
The mucosal component of compound nevi and
intramucosal nevi typically display a characteristic finding
known as histologic maturation. In this event, superficial
“type A” nevus cells with voluminous cytoplasm and
large nuclei “mature” to “type B” nevus cells with less
cytoplasm and smaller nuclei as the lesion extends to the
deeper portions of the dermis. With further descent, “type
C” nevus cells are encountered, which typically have scant
cytoplasm and spindle-shaped nuclei.[4,5]
This paper presents two cases of oral melanocytic nevi.
Immunohistochemistry was used to differentiate the
pattern of nevus cells and their level of maturation in
the tissue.
CASE REPORT
Case 1
A 22-year-old woman was referred to the Department
of Oral Pathology of the institution with the chief
complaint of a pigmented lesion in the right retromolar
region. The patient did not have any significant medical
history. Careful intraoral examination revealed a
smooth, well-circumscribed pigmented lesion in the
right retromolar region. The lesion was brownish-black
in color [Figure 1]. An excisional biopsy was carried out
under local anesthesia and the tissue was examined
histologically.
Figure 1: Case 1 showing pigmented spot in the right retromolar region
30 Indian Journal of Dermatopathology and Diagnostic Dermatology /Vol 2/Issue 2/Jul-Dec 2015
Case 2
A 35-year-old man was referred with the chief complaint
of a pigmented overgrowth in the left buccal mucosa
[Figure 1a]. The patient did not have any significant
medical history. He was a cigarette smoker. On
careful intraoral examination, a brownish-black, well-
circumscribed, exophytic growth near the occlusal line
of left premolar–molar region was seen. The lesion
measured 2 mm × 2 mm. An excisional biopsy was
carried out and the tissue was examined histologically.
The hematoxylin and eosin (H&E) stained section
of both the cases showed hyperplastic stratified
squamous parakeratinized epithelium. The cellular
fibrous connective tissue showed nests of nevus cells
separated by a hyalinized band below the epithelium.
No junctional activity was seen. The nevus cells were
histologically bland without any evidence of dysplasia
[Figures 2 and 3].
Cells at the periphery closer to the epithelium were
large, round without dendritic processes (type A),
and showed intense accumulation of melanin. The
cells in the deeper layers were more uniform, round
to polygonal (type B), and showed decreased melanin
content. Cells in the furthest depth of the lesion were
small and round with spindle-shaped nuclei (type C)
with a total lack of melanin pigment.
The histological features in both the cases were
suggestive of intramucosal nevus.
The sections were stained with Masson Fontana stain
to support the diagnosis. S-100 and HMB-45 antibodies
were used to immunohistochemically delineate the
pattern and type of cells in the nevi.
Figure 1a: Case 2 showing pigmented growth in the left buccal mucosa
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Dutta, et al.: Oral melanocytic nevi: Report of two cases
Masson Fontana stain classically delineated the nevus cells
from the surrounding connective tissue elements [Figure 4].
The absence of junctional activity was confirmed in these
sections. Interestingly “type A” cells (those in the periphery
and least mature) were predominantly stained.
S-100 antibody stained the cells more diffusely with
staining intensity being intense in the peripheral layers
and extending throughout the expanse of nevus cells with
decreasing intensity in the interior regions [Figure 5].
HMB-45 antibody detection was limited to the peripheral
cells with very little reactivity in the center and was
absent in the depth of the lesion [Figure 6].
DISCUSSION
Proliferation of melanocytes, localized or generalized,
may result in an array of pigmented lesions affecting
Figure 2: H&E stained section showing proliferation of nevus cells in Miescher’s
pattern in case 1 Note the junctional separation and differentiation of cells in the
lesion (original magnification 10×)
Figure 4: Masson Fontana stained section of nevus cells. The delineation from
the epithelium and variable staining of cells in the body of the lesion is well-
demonstrated (original magnification ×10)
31 Indian Journal of Dermatopathology and Diagnostic Dermatology /Vol 2/Issue 2/Jul-Dec 2015
the oral mucosa ranging from physiologic (ethnic)
pigmentation, pigmentation associated with smoking
to bland melanotic macules to the most aggressive
melanoma.[6] Evaluation of a patient presenting with a
new pigmented lesion must include a biopsy procedure
other than thorough clinical examination and laboratory
tests, so as to arrive at an accurate diagnosis, notably
if focal oral pigmentation cannot be explained by local
factors. An added advantage of biopsy and histological
examination of the tissue is to aid in differentiation
between an early melanoma that may be easily mistaken
as benign melanocytic nevi.[7]
A pigmented nevus forms a rare cause of focal oral
pigmentation and is a tissue malformation resulting
from excessive proliferation of nevus cells. Three
theories exist to explain the development of the oral
nevi: (1) Abtropfung Theory: This is the classical and the
most widely accepted theory which states that nevus
Figure 3: H&E stained section showing proliferation of nevus cells in Unna’s
pattern in case 2 (original magnification ×10)
Figure 5: S-100 antibody staining reveals most of the cells expressing the
antigen with increased intensity in the top layers near the epithelium (type A
cells) (original magnification ×10)
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Dutta, et al.: Oral melanocytic nevi: Report of two cases
Figure 6: HMB-45 antibody staining reveals intense expression in the type A
peripheral cells with limited expression in type B cells in the body of the lesion
(original magnification ×10)
cells migrate from epidermis to dermis and proliferate
during the development of melanocytic tumors; (2) Dual
Origin Theory: This theory attributes a dual origin to
the nevus cells. Nevus cells located in the basal layer
of the epithelium and juxta-epithelial region of the
submucosa are thought to originate from melanocytes
while nevus cells deep in the dermis or submucosa
are thought to be derived from nerve cells, specifically
Schwann cells. (3) Hochstringerung Theory: This theory
states that melanocytes derived from the neural crest
migrate upwards from the dermis to the epidermis.
Interestingly, this theory reverses the traditional belief of
epidermal origin of nevus cells and is largely supported
by immunohistochemical observations.
Macroscopically, nevi may proliferate in two patterns.
In Unna’s nevi, nevus cells grow in a papillary or round
pattern, giving an exophytic emergence. In Meischer’s
nevi, there is diffuse infiltration of the cells into the
sub-epithelial region giving an endophytic outlook.
The nevus cell per se shares features histologically and
immunohistochemically of both the melanocytes and
neural structures, though lacking in the classic dendritic
processes. The origin of nevus cells in oral melanocytic
nevi is still under confusion. What is definite is the fact
that cell populations have differing levels of maturation.
The staining pattern exhibited in our two cases is
consistent with those reported in literature. The
specificity of HMB-45 antibody in the peripheral
cells (type A) with definitive lack of expression in
the depths of the lesion points to the melanocytic
origin of these cells. The ubiquitous S-100 antibody,
known to stain cells of neural origin including
32 Indian Journal of Dermatopathology and Diagnostic Dermatology /Vol 2/Issue 2/Jul-Dec 2015
melanocytes stained more cellular areas including the
center and depth of the lesion, pointing to presence of
neurological structure origin. The inference seems to
be that the highly differentiated melanocytes lose their
melanocytic expression in the process of maturation
and express the more embryological stable neurological
differentiation in the depths of the lesion. While this
may be argued as dedifferentiation, we prefer to label
it as “change in differentiation.” The retention and
expression of neurological features is a more stable
feature and unlikely to be affected by stimuli that
brought about the change in the first instance. The
lack of cellular differentiation of the nevus cells
vis-à-vis their parent melanocytes also supports
the above observation.
While classical theories of origin have propagated
the migration of melanocytes from the basal layer
of the epithelium to the underlying connective tissue,
the histological presentation of the intramucosal nevi
seems interesting. The lack of connectivity to the basal
layer and the definitive band of connective tissue
that separates the proliferating nevus cells from the
epithelium do not support the concept of epithelial
migration of melanocytes. “Hochstringerung theory”
of dermal proliferation seems more plausible in view
of the histological presentations. Melanocytes derived
from the neural crest are normal components of the
basal layer of the epithelium and juxta-epithelial
layers of the subjacent connective tissue. It is plausible
that stimuli causing proliferation of these cells lead
to a mass of nevus cells that migrate in the region
and tend to push toward the epithelium, probably
because of a common embryological link. Restricted
proliferation incites a connective tissue response
that results in a morphological and immunological
alteration of the cells leading to localization of the
proliferating nevus cells and the formation of an
intramucosal nevus. A more aggressive clone of
nevus cells moves toward the epithelium leading to
junctional activity and the formation of a junctional
nevus. A combination of both the patterns predictably
forms a compound nevus.[1]
The origin and pattern of maturation of the nevus
cells has been discussed previously. In a previous
immunohistochemical study done using S-100,
MIT, and Melan-A antibodies in 12 cases of oral
melanocytic nevi, a strong affinity of the antibodies
to type A cells and a decreased affinity for the type B
cells at the edge of the lesion was noted. The authors
postulated that the subpopulation of cells is a feature
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Dutta, et al.: Oral melanocytic nevi: Report of two cases
of maturation of the lesion and a form of adaptation
to the environment.[4]
In another study of 29 cases of oral melanocytic nevi,
three-fourths of the cells were found to be of type
A while types B and C constituted the rest.[8] Few
multinucleated giant cells were observed, a feature that
was not present in our cases.
Oral melanocytic nevi present an excellent instance
of tissue interactions and embryological influence.
Clinically very few cases are known to undergo malignant
transformation and lesions more likely behave like
a hamartoma. Nevertheless, frequent follow-up after
detection and excision at sites of irritation are advisable.
Financial support and sponsorship
Nil.
Conf licts of interest
There are no conflicts of interest.
33 Indian Journal of Dermatopathology and Diagnostic Dermatology /Vol 2/Issue 2/Jul-Dec 2015
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