Ann Dermatol Vol. 22, No. 1, 2010
DOI: 10.5021/ad.2010.22.1.119
CASE REPORT
A Malignant Melanoma Associated with a Blue Nevus of
the Lip
Hye Young Lee, M.D., So Young Na, M.D., Young Min Son, M.D., Hong Kyu Kang, M.D.,
Jin Ok Baek, M.D., Jong Rok Lee, M.D., Joo Young Roh, M.D.
Department of Dermatology, Gachon University of Medicine and Science, Gil Hospital, Incheon, Korea
Blue nevi are characterized by a collection of pigmentproducing melanocytes in the dermis. These lesions
clinically present as well demarcated cerulean-blue or bluish
black colored papules or plaques that usually measure less
than 1 cm in diameter. They are typically found on the dorsal
surface of the hands and feet or in the head and neck region;
however, they are rarely found in the oral cavity. These
lesions are usually benign and stable over time. However,
malignant melanomas developing in or associated with a
blue nevus (which is also called malignant blue nevus) have
been only rarely reported. A malignant blue nevus might
develop in a common blue or cellular blue nevus, a giant
congenital nevus or in a nevus of Ota, or it may be malignant
from the start. Malignant blue nevi most commonly are
found on the scalp. A malignant blue nevus of the lip has not
been previously reported in the medical literature. We report
here on a patient with a malignant melanoma associated with
a blue nevus of the lip. The malignant melanoma was
presumed to have developed from a blue nevus that was
present on the upper lip of a 50-year-old male. (Ann Dermatol 22(1) 119∼124, 2010)
-KeywordsBlue nevus, Malignant blue nevus, Malignant melanoma,
Upper lip
INTRODUCTION
A blue nevus is a neoplasm that’s composed of pigmented
dendritic dermal melanocytic cells in the reticular dermis.
A blue nevus can develop anywhere on the body; however, about half of the common blue nevi have been
lesions on the dorsal surface of the hands and feet, as well
as on the scalp, and the cellular blue nevi have been
located over the buttocks. Rarely have these lesions been
identified in the oral cavity, yet when they do present in
the oral cavity, they have been reported in the hard palate,
buccal mucosa, upper lip, lower lip and soft palate, in the
order of most common frequency1. A single lesion is
usually identified, but on rare occasions there may be
multiple papules or nodules with satellite lesions that are
mistaken for a malignant melanoma. The blue nevus lesion is considered to be completely benign, but it might
show malignant transformation in rare cases2. Skin biopsy
must be performed for lesions with suspicious malignant
changes such as loss of a regular border and/or the
development of satellite lesions. Malignant melanoma
developing in or associated with a blue nevus is usually
referred to as a malignant blue nevus. However, a
malignant blue nevus may on rare occasions develop in a
giant congenital nevus, a nevus of Ota or it may develop
de novo.
We report here on a 50-year-old male patient with bluish
black macules on the upper lip that had been present for 3
years; recent changes had occurred with ulcerative
nodules and irregular borders, as well as satellite lesions.
Received August 25, 2009, Revised November 3, 2009, Accepted for
publication November 30, 2009
CASE REPORT
Reprint request to: Joo Young Roh, M.D., Department of Dermatology,
Gachon University of Medicine and Science, Gil Hospital, 1198,
Guwol-dong, Namdong-gu, Incheon 405-760, Korea. Tel: 82-32-4602763, Fax: 82-32-460-2001, E-mail: jyroh@gachon.ac.kr
A 50-year-old man presented to the dermatology clinic
with a 3 year history of bluish black macules that were 3
cm in diameter on the upper lip. The skin lesions had
Vol. 22, No. 1, 2010
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HY Lee, et al
Fig. 1. (A) Bluish black macules (arrow head) with irregular borders and (B) ulcerative nodules (arrow) localized on the upper lip
with the development of satellite lesions.
Fig. 2. The histopathological findings of the bluish black macule
showed pigmented spindle-shaped and dendritic melanocytes
among thickened collagen bundles from the reticular dermis
which were close to the epidermis (H&E, ×100).
infiltrative changes with ulcerative nodules and irregular
borders with satellite lesions that had developed within
the past months (Fig. 1). On the initial clinical examination, the skin lesions were localized to the upper lip and
they spared the palate, buccal mucosa and lower lip. No
palpable lymph nodes were detected in the head and
neck region.
Skin biopsies were separately performed on the bluish
black macule and ulcerative nodule. The histopathology
of the bluish black macule (Fig. 2) showed blue nevi
composed of pigmented spindle-shaped and dendritic
melanocytes, and this was associated with alteration of the
collagen architecture in the dermis. The heavily pigmen-
120 Ann Dermatol
ted melanocytes were grouped in an irregular pattern
among thickened collagen bundles in the reticular dermis,
close to the epidermis. The histopathology of the ulcerative nodule (Fig. 3A, B) showed a malignant blue nevus
composed of atypical epithelioid tumor cells with hyperchromatic and polymorphous nuclei in the dermis,
spindle-shaped tumor cells containing dark melanin
granules. There were more cellular epithelioid tumor cells
at the bottom layer that showed frequent mitosis and focal
necrosis (Fig. 3C). A diffuse proliferation of the tumor cells
extended into the deep dermis. In addition, there were
focal atypical large melanocytes arranged as single cells in
the basal layer of the epidermis (Fig. 3D). Any pagetoid
spread of the atypical melanocytes into the upper layer of
the epidermis was not observed. The tumor cells were
predominantly located in the dermis; the drop off sign was
not seen for the tumor cells in the epidermis. Immunohistochemical stains for HMB45 and S-100 proteins
(Fig. 3E, F) were positive in the tumor cells. We performed
staining for CD117 (c-kit) (Fig. 4), which showed diffuse
cytoplasmic staining in the bluish black macule (the blue
nevus component). However, the c-kit expression was
decreased in the cellular epithelioid tumor cells of the
ulcerative nodule (the malignant blue nevus component).
The possibility of metastasis was ruled out by a work-up
that included chest X-ray, whole body PET-CT, neck CT
and gastroscopy; all the results were negative for metastasis. The laboratory chemistry tests, including lactate
dehydrogenase and the liver enzyme activity, were within
the normal range. Wide excision with cervical regional
lymph node dissection was performed. The lymph node
biopsies were negative for metastasis. However, two
months later, the patient presented with a palpable mass
at the left cervical region, and the mass was positive for
A Malignant Melanoma Associated with a Blue Nevus of the Lip
Fig. 3. (A) The histopathologic findings of the bluish black ulcerative nodule showed atypical epithelioid tumor cells and scattered
dark pigmented spindle-shaped cells in the dermis. The findings shown include (B) pleomorphic epothelioid tumor cells intermingled
with pigmented spindle shaped cells, and (C) necrotic tumor cells (arrow) and mitosis (arrow head). (D) Focal atypical large melanocytes
were arranged as single cells on the basal layer of the epidermis without pagetoid spread. The immunohistochemical stains were
positive for HMB45 (E) and S-100 (F) (A: H&E, ×100, B: H&E, ×200, C: H&E, ×400, D: H&E, ×200, E: HMB45, ABC method,
×200, F: S-100, ABC method, ×200).
metastasis to the lymph nodes on the subsequent biopsy
(Fig. 5A). The CD117 (c-kit) staining of the metastatic
lymph nodes was of strong intensity (Fig. 5B). The patient
was treated with a modified radical neck lymph node
dissection and parotidectomy on the left side and he has
been followed for 1 year without any sign of recurrence.
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Fig. 4. CD117 (c-kit) staining of the blue nevus (from the bluish black macule) (A) showed strong positivity and (B) there was a
decreased c-kit expression on the deep invasive part of the malignant blue nevus (from the ulcerative nodule) (A, B: CD 117 stain,
ABC method, ×200).
Fig. 5. (A) Atypical dark pigmented tumor cells have infiltrated the lymph node. (B) The infiltrated tumor cells in the lymph node
showed a strong c-kit expression (A: H&E, ×100, B: CD 117 stain, ×200).
DISCUSSION
Most blue nevi develop on the skin; a blue nevus in the
oral cavity is rare. However, among the nevi of the oral
cavity, blue nevi is the second most common form that
3,4
accounts for 8.3% to 36% of all oral melanocytic nevi .
A blue nevus in the oral cavity typically presents between
the third and fifth decades of life and the hard palate is the
most frequently involved site, followed by the buccal
mucosa, upper lip, lower lip and soft palate1.
Malignant melanomas of the mucosa have been reported
to account for about 3∼4% of all melanomas in the
USA5,6. The head and neck regions are the most frequent
sites of malignant melanoma of the mucosa. The nasal
122 Ann Dermatol
cavity (31.9%) is the most common site, followed by the
oral cavity (23.9%), esophagus (6.3%) and lips (2.8%)6.
The upper part of the oral cavity is the preferred site for a
malignant melanoma of the mucosa. To date, there has
been no direct association between the subtype of oral
melanocytic nevi and oral malignant melanomas.
Malignant blue nevi or malignant melanomas developing
in or associated with a blue nevus are extremely rare.
There has been no reported data regarding the incidence
of these findings, and there are no previous reports of
malignant blue nevi of the oral mucosa or lip. A malignant
blue nevus or malignant melanoma developing in or
associated with a blue nevus had been most commonly
found on the scalp7,8. Hagiwara et al.9 reported on a rare
A Malignant Melanoma Associated with a Blue Nevus of the Lip
case of a 42-year-old woman with a vulvar malignant melanoma and a blue nevus of the cervix.
The common histological features of blue nevi include the
presence of pigmented spindle-shaped and dendritic melanocytes in the dermis, and these melanocytes are associated with alterations of the dermal collagen architecture.
There are three types of benign blue nevi: the common
blue nevus, the cellular blue nevus and the combined
blue nevus, in addition to malignant blue nevi. The
common blue nevus is the most common subtype seen in
the oral cavity1,3 and it is completely benign. However,
cellular blue nevi may be locally aggressive and show
persistence and recurrence after complete excision2,10,11.
Furthermore, there are a few cases where cellular blue
nevi have metastasized to regional lymph nodes10,11.
Some studies have suggested that these cells do not
represent a true metastasis, but rather, they were passively
transported to the lymph nodes11. However, some of these
lesions may best be interpreted as atypical cellular blue
nevi or cellular blue nevi with atypical features and an
indeterminate biological potential10,11. Atypical cellular
blue nevi are characterized by features that include architectural atypia (an infiltrative margin and/or asymmetry)
and/or cytologic atypia (hypercellularity, nuclear pleomorphism, hyperchromasia, occasional mitotic figures and/or
subtle necrosis)12. The absence or scarcity of mitotic figures, necrosis and high-grade atypia is not consistent
with a malignant blue nevus. The presence of areas of
dendritic blue nevi type cells elsewhere in the tumor and
the absence of an intraepidermal component are not
suggestive of a melanoma. Malignant blue nevi show a
combination of high grade atypia, spontaneous tumor
necrosis and more than a few mitoses. However, some
lesions do not meet all of these criteria and they show
overlap with atypical cellular blue nevi with regional
metastasis10,11.
There is some dispute as to whether the malignant blue
nevus should be considered a separate entity from a
melanoma or if it should be simply referred to as a
malignant melanoma developing in or associated with a
blue nevus10,11. Malignant blue nevi differ from primary
melanomas by the absence of junctional activity and the
presence of associated blue nevi13. According to Unna’s
‘Abtropfung theory’ (trickling down theory), nevus cells of
an epidermal origin drop off into the dermis and there
they form clusters or nests. This phenomenon is commonly seen when primary melanomas invade into the
dermis during the vertical growth phase14. In our case,
there were focal atypical melanocytes arranged in the
basal layer of the epidermis without dropping off into the
dermis. These findings were different from the junctional
activity seen in melanomas during the vertical growth
phase, and our patient’s lesions showed the following
characteristics: 1) atypical melanocytes were arranged as
single cells that did not form clusters or nests; 2) the
findings were focal without pagetoid spread of the
malignant tumor cells into the upper layer of the epidermis.
The pathogenesis of malignant blue nevi is not well
known. Tumor cells incubated with DOPA have been
found to have strongly positive responses, demonstrating
that the tumor cells are melanocytes in origin. A tyrosine
kinase receptor encoded by the c-kit gene (CD117) has
been reported to be important in the proliferation of
melanocytes15,16. The expression of the c-kit gene is strong
in normal junctional melanocytes and in the junctional
component of compound nevi. The level of c-kit is decreased in the dermal component of nevi16. The benign or
in-situ components of malignant melanomas are positive
for c-kit and they are negative within the invasive part,
and the c-kit expression is lost during progression13,16-18.
Zyrek-Betts et al.13 reported a patient with a malignant
blue nevus and lymph node metastases with CD117 (c-kit)
immunohistochemical staining. CD117 staining of the
cellular blue nevi component was strongly positive and
this was decreased in the dermal component of the
invasive melanoma. However, it showed up-regulation in
the metastatic lymph nodes, which is unlike the prior
reports that have shown a decreased c-kit expression in
the metastatic melanoma16-18. Our patient presented with
similar findings that were consistent with the case reported by Zyrek-Betts et al.13. These findings suggest that
malignant blue nevi are different from other melanomas in
their biological behavior.
Our case is unique with regard to the histological features
of malignant melanoma that presumably developed in the
blue nevus of the lip. The lesion met all the criteria with
high grade atypia, spontaneous tumor necrosis (shown as
ulcer clinically) and frequent mitoses. Malignant blue nevi
might develop from blue or cellular blue nevi, a giant
congenital nevus or in a nevus of Ota, or it may be malignant from the start. In our case, we assumed that the blue
nevus was malignantly transformed because our patient
had a stable pigmented macule on the lip without any
changes in shape, size and color for 3 years. The malignant changes, including ulceration and irregular borders,
developed over a short period of time. Furthermore, the
c-kit expression was decreased in the deep invasive part of
the lesion, as opposed to the superficial and peripheral
components of the malignant blue nevus. These findings
support the suggestion that the c-kit expression is lost
during malignant progression17,18.
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The prognosis for a malignant blue nevus has varied for
both metastasis and survival in different series; this tumor
is considered an aggressive lesion with a metastasis rate of
up to 83% and a mortality rate of 67∼73%19,20. Although
there are discrepancies with regard to the rates of
metastasis depending on the study, it is clear that this
lesion has a poor prognosis.
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