ARTICLE
Auteur(s) : Noriyuki
Misago1, Kohtarou Nagase2, Shuji
Toda2, Yohsuke Shinoda1, Shinich
Koba1, Yutaka Narisawa1
1Division of Dermatology, Department of Internal
Medicine, Faculty of Medicine, Saga University, Nabeshima 5-1-1,
Saga 849-8501, Japan
2Department of Pathology, Faculty of Medicine, Saga
University, Saga, Japan
accepté le 13 Mai 2008
A cellular blue nevus is an infrequent, relatively large, benign
melanocytic lesion, which is located most frequently over the
buttock/sacrococcygeal region and usually develops during birth or
childhood [1]. The most important issues in treating cellular blue
nevi are; 1) the existence of some diagnostically challenging cases
involving a differential diagnosis of melanomas and several
variants of blue nevi or related lesions [2], such as a recently
described pigmented epithelioid melanocytoma (animal-type
melanoma/epithelioid blue nevus) [3], and 2) the rare involvement
of the local lymph nodes, which is referred to as “benign
metastasis” [4-11]. Recent investigators, however, have claimed
that the older literature on cases with “benign metastasizing”
cellular blue nevi was not well illustrated and some of the
well-illustrated cases are actually examples of a melanoma or
pigmented epithelioid melanocytoma [3, 12]. A further literature
review also revealed that specific cases of a cellular blue nevus
involving the local lymph nodes are rare. This study describes a
typical case of a cellular blue nevus with nevus cells in a
sentinel lymph node.
Case report
A 34-year-old male presented with a bluish nodule that had been
present on his buttocks since childhood. Although no evident
clinical changes in the nodule were seen, he visited a dermatology
clinic for the nodular lesion. An incisional biopsy was performed
by the dermatologist and a diagnosis of a cellular blue nevus or
melanoma (including malignant blue nevus) was made. A complete
excisional biosy was recommended and he was referred to this
clinic. A clinical examination revealed a gray to bluish, slightly
elevated, cutaneous to subcutaneous nodule, measuring 30 mm ×
25 mm, on his right buttock neighboring the sacrococcygeal
region (figure
1A). No clinically palpable, regional lymph nodes were
seen. He chose to receive therapy through an excisional biopsy for
the nodular lesion, in consideration of a spreading melanoma.
Preoperative lymphoscintigraphy was performed using technetium
99m-tin colloid, which demonstrated one sentinel lymph node in the
right inguinal region (figure 1B). After removal
of the sentinel lymph node, the nodular lesion on the buttock was
excised with a 2-cm safety margin (figure 1C). The
histopathological examination revealed the excised nodule to be a
well-circumscribed, pigmented nodule, which was located in both the
dermis and the subcutaneous tissue (figure 2A). The lesion
showed a biphasic pattern characterized by areas of deeply
pigmented dendritic melanocytes alternating with nodular islands or
fascicles, which were composed of spindle-shaped cells with
abundant pale or eosinophilic cytoplasm and small to moderate
amounts of melanin (figure 2). These
constituent cells were surrounded by abundant melanophages.
Sclerotic areas were frequently observed in the stroma. Neither
marked pleomorphism nor atypical mitoses were seen in the
constituent cells and no areas of necrosis were observed. The
histopathology of the sentinel lymph node disclosed several areas
composed of deeply pigmented, dendritic and spindle-shaped cells
located in the capsule and rarely in the fibrous trabeculae (figure 3A).
Immunohistochemistry was performed with an alkaline phosphatase
detection system using the following antibodies against S-100
protein, HMB45, Melan-A, c-kit (CD117), CD68, Ki-67, and the
proliferating cell nuclear antigen (PCNA). The pigmented cells in
the lymph node as well as constituent cells in the cutaneous lesion
were immunohistochemically positive for S-100 protein, HMB45,
Melan-A, and c-kit (figure 3B and C). No Ki-67
positive cells were seen in either the cutaneous or lymph node
lesions (figure
3D), and PCNA was present in 5% of the cutaneous lesional
cells and only a few cells of the nodal lesional cells in the
capsule. Many melanophages, which were confirmed by positive
staining for CD68 and negative staining for S-100 protein and Melan
A, were seen in the parenchyma of the lymph node. However, only a
few, isolated, plump pigmented cells, which were positive for S-100
protein, HMB45, Melan-A, and negative for CD68 (figure 3E and F), were
also seen in the parenchyma. These cells were not seen, however, in
the sections for the staining of c-kit, Ki-67, and PCNA. Based on
these histopathological findings, the diagnoses of a cellular blue
nevus and nevus cells in the sentinel lymph node were made, and no
further treatment was performed. Neither recurrence nor metastasis
was seen during a 2-year follow-up.
Discussion
The observation of nevus cells in the lymph nodes has been
well-documented. These conditions are generally classified as
either nodal nevus cell aggregates [13-17] or nodal blue nevus
[18-22]. The nevus cells of the former are similar to the cells of
the intradermal type of melanocytic nevi and those of the latter
resemble the pigmented dendritic cells seen in common blue nevi
[13-22]. As a rule, these conditions are incidentally found
associated with the removed lymph nodes removed during a surgical
procedure, especially in female mammary carcinomas and melanomas.
However, nodal nevus cell aggregates have been suggested to be
related to melanocytic nevi (in particular congenital nevi) in the
draining skin [14, 17], and a rare case of nodal blue nevus
associated with a common blue nevus in the regional skin has also
been reported [18].
The best documented cases, which showed an association of nodal
nevus cells with melanocytic lesions in the regional skin, are the
examples of cellular blue nevus [4-11]. One older study reported
that 5.2% of the total number of published cases of cellular blue
nevus had regional “metastasis” to lymph nodes [1]. Nevus cells in
lymph nodes (nodal nevus cell aggregates and nodal blue nevus)
usually demonstrate a benign type of location. The nevus cells are
limited to the capsule with occasional extension to the fibrous
trabeculae [13-22], except for very rare examples with involvement
in the parenchyma [23]. In contrast, with the exception of a one
case [6], most of the reported cases of cellular blue nevus with
lymph node involvement showed the location of nevus cells in the
subcapsular (marginal) sinuses and parenchyma of the lymph nodes.
This malignant type of location is observed in metastatic melanoma
cells. However, among these reported cases, there were no specific
cases of cellular blue nevus demonstrating a typical biphasic
pattern, as has recently been suggested by some investigators [3,
12].
This report presented a case of a cellular blue nevus with the
typical biphasic pattern, demonstrating that the cellular blue
nevus surely involved the regional lymph node. In contrast to
previous reports, most of the nevus cells in the present nodal
lesion were limited to the capsule. This benign type of location is
considered to be acceptable because a cellular blue nevus is
benign. Meanwhile only a few, isolated nevus cells which were
confirmed based on their positivity to S-100 protein, HMB45,
Melan-A and negativity for CD68, were also seen in the parenchyma
of the lymph node. The nevus cells observed in the parenchyma were
considered to have two possible origins; namely, 1) the possible
displacement of nevus cells in the parenchyma as a consequence of
the incisional biopsy, and 2) the possibility that these traveling
nevus cells in the parenchyma are actually metastasizing malignant
or pre-malignant cells. Although we diagnosed the present case to
be a typical cellular blue nevus, a recent study has indicated that
there is currently substantial confusion and disagreement among
experienced histopathologists about the definitions and biological
nature of the spectrum of cellular blue melanocytic neoplasms;
which include cellular blue nevus, cellular blue nevus with
atypical features or indeterminate malignant potential (so-called
atypical cellular blue nevus), and malignant melanoma either
resembling or associated with cellular blue nevus (malignant blue
nevus) [24]. We should therefore be cautious about definitely
concluding that the present case is not a melanoma, but instead
consider that it might possibly be a low grade melanoma.
Although the pathogenesis of the nevus cells in lymph nodes has
not yet been clarified, the following two views have been
advocated; a developmental arrest of melanocytes migrating from the
neural crest and the so-called “benign metastasis” [13-22]. The
former view is consistent with the benign type of the location in
lymph nodes, and the fact of the occurrence of blue nevi in the
prostate, cervix, vagina, and spermatic cord. The latter view is
supported by the observation of lymphatic invasion in melanocytic
nevi [25], and a higher incidence of nevus cell aggregates in
sentinel lymph nodes than non-sentinel lymph nodes [26, 27].
No prior studies describing the detailed immunohistochemical
findings in the nodal cellular blue nevus cells have been made in
contrast to recent immunohistochemical investigations on nodal
nevus cell aggregates [23, 28]. Except for positive staining for
HMB45, these findings in the nodal cellular blue nevus cells
presented were closely correlated with those in the nodal nevus
cell aggregates; namely, S-100 protein+, Melan-A+, and Ki-67-
immunophenotype [23, 28]. In addition to the positive reaction of
c-kit in cellular blue nevus cells in the skin lesion according to
the findings of a previous report [29], the present study also
demonstrated an expression of c-kit (CD117) by the nevus cells in
the lymph node. c-kit is expressed in the melanocyte precursors of
the neural crest cells, and these c-kit positive cells migrate into
the epidermis from the neural crest [30]. The migrating melanocytes
in the lymph node are expected to express c-kit [30]. The c-kit
expression in the present nodal nevus cells may also suggest the
benign nature of the nodal nevus cells, because the c-kit
expression is usually lost in metastatic melanoma cells [29,
31].
The diagnostic difficulties associated with a cellular blue
nevus include the differentiation from pigmented epithelioid
melanocytoma (low-grade variant of melanoma with frequent lymph
node metastases but an indolent clinical course) [3] as well as the
spectrum of cellular blue melanocytic neoplasms [3, 24]. The case
presented showed that the nodal involvement of a cellular blue
nevus may also be confusing, because the nevus cells were located
in both the capsule and the parenchyma although there were only a
few nevus cells in the parenchyma. In cellular blue nevi or lesions
with similar histopathological features, however, it may be
appropriate to consider the predominant involvement of the capsule
as well as the benign cytological features and the
immunohistochemical profiles (Ki-67–, PCNA–, and c-kit+) of the
nodal cells to be a benign sign.
In any case, considering the diagnostic difficulties in the
spectrum of cellular blue melanocytic neoplasms [24] and the
possibility of either a malignant transformation or a low grade
malignant potential in such a cellular blue nevus [24, 32], a
sentinel lymph node biopsy is therefore recommended in all dubious
cellular blue nevus lesions and it may further be recommended even
in these typical lesions. The reason for such a recommendation is
due to the fact that a malignant blue nevus is highly aggressive
and when it is diagnosed, it is usually too late for any treatment
to be performed [33].
Acknowledgements
Financial support: none. Conflicts of interest: none.
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