Pediatric and Developmental Pathology 2, 473–477, 1999
r1999 Society for Pediatric Pathology
Adnexal-Centered Giant Congenital
Melanocyte Nevus with Extensive
Ganglioneuromatous Component
and Trisomy 7
RICARDO DRUT,* ROSA MÓNICA DRUT,
Department of Pathology, Hospital de Niños ‘‘Superiora Sor Marı́a Ludovica,’’ 1900 La Plata, Argentina
Received June 12, 1998; accepted October 13, 1998.
ABSTRACT
Adequate interpretation of clinical and histopathologic
features of giant congenital melanocytic nevus (GCMN)
in newborns is a continued challenge. A GCMN with
three large nodules and three polypoid exophytic tumors
presented in the dorsum of a female full-term newborn,
the borders exhibiting a spotted grouped pattern. Micro-
scopic examination revealed a peculiar adnexal-centered
(eccrine sweat gland ducts, acrosiringia, and hair infun-
dibula) compound nevus expressing pagetoid intraepider-
mal spreading of epithelioid melanocytes. The nodules
represented an extensive ganglioneuromatous compo-
nent. The neurons and their neuropil were positive for
neuron-specific enolase, S-100, synaptophysin, tyrosine
hydroxilase, and PGP 9.5. In addition to these compo-
nents, a poorly differentiated, fusiform, low-mitotic rate
population of cells undergoing epithelioid differentiation
(and probably neuronal differentiation) with nodular
arrangement was also present in the polypoid tumors
and deeper parts of the nevus, in part intermixed with the
neurons. These cells were vimentin positive but S-100
negative. FISH studies revealed these cells to express
three signals for the centromeric probe for chromosome
7 whereas the neuronal component showed just two.
Adnexal-centered arrangement of melanocytes has not
been emphasized in GCMN. Ganglioneuromatous differ-
entiation has been rarely reported in this condition.
Trisomy 7 in GCMN has been reported only once previ-
ously.
*Corresponding author
Pediatric and Developmental Pathology
AND MARTA COHEN
Key words: adnexal-centered nevus, ganglioneuroma,
giant congenital melanocyte nevus, trisomy 7
INTRODUCTION
Giant congenital melanocyte nevi (GCMN) are
peculiar neural crest–related hamartomatous le-
sions that cover large areas of the skin [1,2].
Recently, trisomy 7 has been recognized to be
present in this lesion [3]. GCMN consistently create
difficulties in treatment, are of cosmetic and psycho-
social significance for the patient and relatives, and
probably imply an increased risk for the develop-
ment of melanoma as well as other malignancies
[1,2,4]. Notably, some GCMN may present clini-
cally as alarming-looking tumors. This, combined
with the fact that early neonatal biopsies of GCMN
may show many of the microscopic features ac-
cepted for the diagnosis of melanoma in older
patients [5,6], may induce the diagnosis of malig-
nancy. Those features include at least the following:
(1) presence of intraepidermal isolated or grouped
epithelioid melanocytes at all levels simulating
superficial spreading melanoma, and (2) appear-
ance of proliferative dermal nodular collections of
epithelioid and spindle-shaped cells, occasionally
heavily pigmented, suggesting nodular melanoma
[1]. In addition to this, GCMN may present with
ulcerated areas and/or include grossly visible polyp-
oid exophytic tumors of different size [2]. GCMN or
multiple CMN may represent the surface compo-
nent of a rare congenital disorder known as neuro-
cutaneous melanocytosis, in which the meninges
present benign or malignant melanocytic tumors
[2,7]. A peculiar variant of GCMN, namely bulky
naevocytoma of the perineum, presents as a large,
pigmented tumor in the perineal region [8].
Eccrine-centered nevus is a particular variant
of CMN, first described by Mishima [9], in which
the nevus cells arrange around and in the eccrine
sweat ducts. Cases reported clearly indicate that
this particular disposition of the nevus cells always
presents in examples of CMN [10]. However, we
have not been able to find any reference indicating Figure 1. Very large, pigmented congenital nevus at
such a pattern in GCMN. The case we report here the dorsum showing two of the nodules and three
polypoid tumors. The border has the typical spotted
was also associated other neural crest–related tis-
grouped pattern.
sues in the deeper part, in particular, an extensive
ganglioneuromatous component, a situation rarely
referred to in the literature [11,12].
PATHOLOGY FINDINGS
Histologic examination of the detached original
CASE REPORT mass as well as of the polypoid tumors resected
This newborn presented at birth with a large, afterward showed an array of spindle-shaped cells
in tight or loosely arranged groups with low mitotic
deeply black giant nevus of 15 ⫻ 9 cm, involving the
rate (1–3/10 high power fields). These cells were
dorsal aspect of the trunk from D6 to L3, and
focally associated with osteoid deposits and inter-
extending laterally to the posterior axillary line on
mixed with melanin-containing isolated or grouped
both sides. Most of the surface of the nevus was flat.
epithelioid melanocytes. Part of the surface was
Also present were three heavily pigmented nodules,
devoid of epidermis and covered by fibrin and
the larger being 2.5 cm in diameter, and three
leukocytes. The spindle cells of the tumoral lesions
pinkish polypoid masses showing eroded surface
were positive for vimentin and S-100 and negative
(Fig. 1). One similar 1.5-cm tumor had autoampu-
for skeletal muscle–specific actin (HHF-35). Flat
tated spontaneously during labor and was sent to
areas of the nevus showed that the epidermis
the pathology department by the acting obstetri-
contained junctional nests, basal hyperplasia, as
cian. The patient was referred to our hospital and well as all levels of intraepidermal epithelioid mela-
admitted to the neonatal care unit. Clinical, imag- nocytes, many of them heavily loaded with melanin
ing, and laboratory studies were unremarkable, granules. The junctional activity was particularly
except for the dorsal nevus and three pinpoint- striking at the acrosiringia, the upper intradermal
sized pigmented lesions localized to the right fron- segment of the eccrine sweat ducts, and the hair
tal region, second right finger, and left pretibial infundibula, a finding that was consistent in all the
region. Two polypoid masses were extirpated and samples obtained from the rest of the nevus. Sev-
submitted for histologic study along with a biopsy eral samples obtained from the nodules of the last
of the lower margin of the main GMN. A complete large surgical specimen involving the whole GCMN
resection of the nevus, including the superficial revealed that extensive areas of the dermal compo-
fascia and some skeletal muscle fibers, was per- nent of the lesion were represented by large cells
formed 10 days after admission, at the age of 20 with ganglionar differentiation with nuclei exhibit-
days. Six months after surgery the patient is alive ing prominent nucleoli in a notably fibrillary back-
and well. ground (Fig. 2). The picture strongly suggested a

474 R. DRUT ET AL.

Figure 2. Extensive ganglioneuromatous replacement
of the hypodermis and lower dermis. Inset: Sharp neuro-
nal cytoplasmic and nuclear S-100 positivity. Hematoxy-
lin and eosin, ⫻50; inset, ⫻80.
ganglioneuromatous appearance. These areas also
exhibited frequent, very ectatic vessels with thin
walls. The neurons and the fibrillary background
were neuron-specific enolase, synaptophysin, PGP
9.5, tyrosine hydroxilase, and S-100 positive (Fig. 2,
inset). The S-100 immunoreactivity produced the
sharpest contrast with the rest of the tissues pre-
sent in the lesion. The rest of the dermis and
hypodermis was occupied by tight fascicles, focally
in concentric whorls, of spindle-shaped or more
loosely arranged epithelioid cells. Also present were
melanocytes containing different amounts of mela-
nin, arranged in a collagenous interstitial matrix.
Upper levels presented large, melanin-containing
nevus cell groups. A few spindle and stellate cells
present in the perivascular loose myxomatous tis-
sue proved to react positively for epithelial mem-
brane antigen (EMA).
Fluorescent in situ hybridization (FISH) stud-
ies performed with the pericentromeric probe for
chromosome 7 (D7Z1) on paraffin-embedded tis-
sue sections revealed the presence of three signals
in 70% of the nuclei of the nevus cells and two
signals in the ganglion cells (Fig. 3). Thus only the
undifferentiated nevus cells showed an extra chro-
mosome 7.
DISCUSSION
GCMN may contain a large variety of constituent
cells [4]. Clinically alarming GCMN containing
heavily cellular tumoral masses suggesting malig-
nancy but behaving in a benign manner have
Figure 3. Composite figure showing nevus cell nuclei
with three fluorescent signals for the pericentromeric
region of chromosome 7.
already been referred to in the literature [1]. This
discordance justifies the recommendation of ex-
treme caution before making the diagnosis of malig-
nancy in any such nevi during the first months of
life [1,12,13]. Hendrickson and Ross [4] reported
seven patients developing neoplasms in GCMN.
Remarkably, the three infants presenting in their
first year of life did not present late recurrences or
metastasis. On the other hand, true malignant,
metastasizing tumors may arise in CMN, giant or
not. The list includes melanomas [1,4], which may
be congenital (see ref. 2 for review), and rhabdomyo-
sarcoma [14,15]. Poorly differentiated small round-
cell malignancies as well as unclassified undifferen-
tiated sarcomas have also been reported [4]. A
combination of these histologic patterns may be
found [4]. CMN may develop tumors, either benign
or malignant, expressing any or several of the
differentiating capabilities of the neural crest [1,2,4],
the lesion fitting very well in the group of so-called
neurocristopathies [16]. An unusual example of
this was reported by Roth et al. [17]. Their patient
was a 16-month-old girl with a history of partially
excised GCMN who developed a retroperitoneal
‘‘malignant schwannoma with melanocytic and neu-
roepithelial differentiation.’’ Although the authors
suggest that the lesions were not in continuity, no
autopsy was performed to clearly establish the
possibility that the CMN had had a deep compo-
nent. Recently, the term ‘‘plutipotential melanoblas-
GIANT NEVUS 475
toma’’ has been proposed to encompass the wide
range of malignancy types that may present in
GCMN [18]. The authors suggest that these diver-
gent differentiation lines recapitulate those nor-
mally expressed by the neural crest cells.
Although the multicentric polypoid tumors
present in our patient were clinically spectacular,
most of their constituent spindle cells were positive
for only vimentin and S-100. Hence, the lesions
were interpreted as being composed of undifferen-
tiated ectomesenchymal cells. The presence of oste-
oid deposits suggests osteogenic differentiation,
while the recognition of a small proportion of cells
expressing positivity for EMA may be interpreted
as meningeal–perineurial differentiation; both of
these findings are in line with neural crest anlage
potentialities.
The present case expressed yet two other
unusual features for GCMN, both of which deserve
comment—namely adnexal-centered junctional ac-
tivity and a ganglioneuromatous dermal compo-
nent. As mentioned above, adnexal-centered mela-
nocytic nevi include CMN containing junctional
nests associated with the upper portion of the
eccrine sweat ducts and hair infundibula [9,10].
This peculiar localization has not been described in
acquired melanocytic nevi. Most of the eccrine-
centered nevus cases, if not all, present clinically as
spotted, grouped pigmented nevi [9,10]. Some of
these also exhibit hair infundibula involvement
[10]. However, the adnexal-centered distribution of
the junctional nests seems not to have been re-
ported in GCMN, as found in this case. Interest-
ingly, it was only at the periphery of the lesion that
the spotted grouped pattern of pigmentation was
evident (Fig. 1). The extensive ganglioneuromatous
dermal component was another unexpected find-
ing. Groups of ganglion cells in GCMN have been
previously reported by Masson [11] in a 7-year-old
child with a large lesion affecting the right half of
his face; the lesion was interpreted as a ‘‘sympa-
thetic and melanogenic ganglioneurofibroma of
the skin.’’ Slaughter et al. [12] mentioned the
presence of ganglion cells as part of a GCMN of the
dorsum in a 1-year-old boy with neurocutaneous
melanosis who died from what seems to be the first
reported example of metastatic rhabdomyosar-
coma arising in a GCMN.
476 R. DRUT ET AL.
Figure 4. Peculiar blastematous-like, concentric arrange-
ment of undifferentiated spindle-shaped cells, in part
surrounding small vessels. Inner cells show more epitheli-
oid appearance. Arrow points to cells with features
suggesting early neuronal differentiation: nucleus with
open chromatin and prominent nucleolus. Insets: Cells
interpreted as representing early stages of neuronal
differentiation. Hematoxylin and eosin, ⫻100; insets,
⫻400.
Closer examination of the ganglioneuro-
matous differentiation in our case revealed that
the general picture could be arranged in the follow-
ing sequential steps of differentiation. First, fas-
cicles of spindle-shaped cells acquired concentric,
onion-skinned disposition in groups of 10 to 20
layers exhibiting a blastematous appearance. Sec-
ond, at the center of the latter, cells progressively
showed epithelioid features and later on, early
neuronal differentiation (Fig. 4). The next step
included the appearance of nests of full-blown
ganglionar cells, which progressively became sur-
rounded by fibrillary neuropil. These steps were
recognizable up to the mid-dermis. The peculiar
distribution of the ganglion cells, limited to the
deeper dermis and hypodermis, together with the
proposed steps of differentiation favors the interpre-
tation that in the tumoral areas of this GCMN, the
undifferentiated cells were committed to neuronal
and melanocytic differentiation. FISH findings of
this case confirm a preliminary report [3] describ-
ing the presence of an extra copy of chromosome 7
in the CMN.
NOTE ADDED IN PROOF
The relationships between nevus cells and ganglio-
neuromatous differentiation are also emphasized
by a recent report of ganglioneuroblastic differen-
tiation of melanoma cells metastatic to an inguinal
lymph node [19].
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