Adnexal-centered Giant Congenital

Pediatric and Developmental Pathology 2, 473–477, 1999

Pediatric and Developmental Pathology

r1999 Society for Pediatric Pathology

Adnexal-Centered Giant Congenital Melanocyte Nevus with Extensive Ganglioneuromatous Component and Trisomy 7 RICARDO DRUT,* ROSA MO´ NICA DRUT,

AND

MARTA COHEN

Department of Pathology, Hospital de Nin˜os ‘‘Superiora Sor Marı´a 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. Microscopic examination revealed a peculiar adnexal-centered (eccrine sweat gland ducts, acrosiringia, and hair infundibula) compound nevus expressing pagetoid intraepidermal spreading of epithelioid melanocytes. The nodules represented an extensive ganglioneuromatous component. The neurons and their neuropil were positive for neuron-specific enolase, S-100, synaptophysin, tyrosine hydroxilase, and PGP 9.5. In addition to these components, 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 differentiation has been rarely reported in this condition. Trisomy 7 in GCMN has been reported only once previously.

*Corresponding author

Key words: adnexal-centered nevus, ganglioneuroma, giant congenital melanocyte nevus, trisomy 7

INTRODUCTION Giant congenital melanocyte nevi (GCMN) are peculiar neural crest–related hamartomatous lesions 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 psychosocial significance for the patient and relatives, and probably imply an increased risk for the development of melanoma as well as other malignancies [1,2,4]. Notably, some GCMN may present clinically as alarming-looking tumors. This, combined with the fact that early neonatal biopsies of GCMN may show many of the microscopic features accepted for the diagnosis of melanoma in older patients [5,6], may induce the diagnosis of malignancy. 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) appearance 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 component of a rare congenital disorder known as neurocutaneous 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 such a pattern in GCMN. The case we report here was also associated other neural crest–related tissues in the deeper part, in particular, an extensive ganglioneuromatous component, a situation rarely referred to in the literature [11,12].

CASE REPORT This newborn presented at birth with a large, deeply black giant nevus of 15 ⫻ 9 cm, involving the dorsal aspect of the trunk from D6 to L3, and extending laterally to the posterior axillary line on both sides. Most of the surface of the nevus was flat. Also present were three heavily pigmented nodules, the larger being 2.5 cm in diameter, and three pinkish polypoid masses showing eroded surface (Fig. 1). One similar 1.5-cm tumor had autoamputated spontaneously during labor and was sent to the pathology department by the acting obstetrician. The patient was referred to our hospital and admitted to the neonatal care unit. Clinical, imaging, and laboratory studies were unremarkable, except for the dorsal nevus and three pinpointsized pigmented lesions localized to the right frontal region, second right finger, and left pretibial region. Two polypoid masses were extirpated and submitted for histologic study along with a biopsy of the lower margin of the main GMN. A complete resection of the nevus, including the superficial fascia and some skeletal muscle fibers, was performed 10 days after admission, at the age of 20 days. Six months after surgery the patient is alive and well. 474

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Figure 1. Very large, pigmented congenital nevus at the dorsum showing two of the nodules and three polypoid tumors. The border has the typical spotted grouped pattern.

PATHOLOGY FINDINGS Histologic examination of the detached original mass as well as of the polypoid tumors resected afterward showed an array of spindle-shaped cells in tight or loosely arranged groups with low mitotic rate (1–3/10 high power fields). These cells were focally associated with osteoid deposits and intermixed with melanin-containing isolated or grouped epithelioid melanocytes. Part of the surface was devoid of epidermis and covered by fibrin and leukocytes. The spindle cells of the tumoral lesions were positive for vimentin and S-100 and negative for skeletal muscle–specific actin (HHF-35). Flat areas of the nevus showed that the epidermis contained junctional nests, basal hyperplasia, as well as all levels of intraepidermal epithelioid melanocytes, many of them heavily loaded with melanin granules. The junctional activity was particularly striking at the acrosiringia, the upper intradermal segment of the eccrine sweat ducts, and the hair infundibula, a finding that was consistent in all the samples obtained from the rest of the nevus. Several samples obtained from the nodules of the last large surgical specimen involving the whole GCMN revealed that extensive areas of the dermal component of the lesion were represented by large cells with ganglionar differentiation with nuclei exhibiting prominent nucleoli in a notably fibrillary background (Fig. 2). The picture strongly suggested a

Figure 2. Extensive ganglioneuromatous replacement of the hypodermis and lower dermis. Inset: Sharp neuronal cytoplasmic and nuclear S-100 positivity. Hematoxylin 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 present 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 melanin, 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 tissue proved to react positively for epithelial membrane antigen (EMA). Fluorescent in situ hybridization (FISH) studies performed with the pericentromeric probe for chromosome 7 (D7Z1) on paraffin-embedded tissue 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 chromosome 7.

DISCUSSION GCMN may contain a large variety of constituent cells [4]. Clinically alarming GCMN containing heavily cellular tumoral masses suggesting malignancy 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 extreme caution before making the diagnosis of malignancy 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 rhabdomyosarcoma [14,15]. Poorly differentiated small roundcell malignancies as well as unclassified undifferentiated 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 neuroepithelial 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 component. Recently, the term ‘‘plutipotential melanoblasGIANT NEVUS

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toma’’ has been proposed to encompass the wide range of malignancy types that may present in GCMN [18]. The authors suggest that these divergent differentiation lines recapitulate those normally 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 undifferentiated ectomesenchymal cells. The presence of osteoid 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 activity and a ganglioneuromatous dermal component. As mentioned above, adnexal-centered melanocytic 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 eccrinecentered 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 reported in GCMN, as found in this case. Interestingly, 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 finding. 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 ‘‘sympathetic 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 rhabdomyosarcoma arising in a GCMN.

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Figure 4. Peculiar blastematous-like, concentric arrangement of undifferentiated spindle-shaped cells, in part surrounding small vessels. Inner cells show more epithelioid 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 ganglioneuromatous differentiation in our case revealed that the general picture could be arranged in the following sequential steps of differentiation. First, fascicles of spindle-shaped cells acquired concentric, onion-skinned disposition in groups of 10 to 20 layers exhibiting a blastematous appearance. Second, 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 surrounded 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 interpretation 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] describing the presence of an extra copy of chromosome 7 in the CMN.

NOTE ADDED IN PROOF The relationships between nevus cells and ganglioneuromatous differentiation are also emphasized by a recent report of ganglioneuroblastic differen-

tiation of melanoma cells metastatic to an inguinal lymph node [19]. R EFERENCES 1.

2. 3.

4.

5.

6.

7.

8.

9.

Elder DE, Murphy GF. In: Melanocytic tumors of the skin. Atlas of Tumor Pathology. Washington, DC: Armed Forces Institute of Pathology, 1991;64–78. Isaacs H Jr. Tumors of the Fetus and Newborn. Philadelphia: W.B. Saunders, 1997;114–119. Alvarez-Franco M, Vicari FA, Reyes-Mugica M, Bauer BS. Extra chromosome 7 is present in congenital pigmented nevi [abstract]. Pediatr Pathol 1994;14:359. Hendrickson MR, Ross JC. Neoplasms arising in congenital giant nevi. Morphologic study of seven cases and a review of the literature. Am J Surg Pathol 1981;5:109–135. Mancianiti ML, Clark WH, Hayes FA, Herlyn M. Malignant melanoma stimulants arising in congenital melanocytic nevi do not show experimental evidence for a malignant phenotype. Am J Pathol 1990;136:817–829. Angelucci D, Natali PG, Amerio PL, Ramenghi M, Musiani P. Rapid prenatal growth mimicking malignant transformation in a giant congenital melanocytic nevus. Hum Pathol 1991;22:297–301. Reyes-Mugica M, Chou P, Byrd S, et al. Nevomelanocytic proliferations in the central nervous system of children. Cancer 1993;72:2277–2285. Reyes-Mugica M, Gonzalez-Crussi F, Bauer BS, MedinaEscobedo G. Bulky naevocytoma of the perineum: a singular variant of congenital giant pigmented naevus. Virchows Arch (A) 1992;420:87–93. Mishima Y. Eccrine-centered nevus. Arch Dermatol 1973; 107:59–61.

10. Morishima T, Endo M, Imagawa Y, Morioka S. Clinical and histopathological studies on spotted grouped pigmented nevi with special reference to eccrin-centered nevus. Acta Derm Venereol (Stockh) 1976;56:345–351. 11. Masson P. Melanogenic system: nevi and melanomas. Pathol Annu 1967;2:351–397. 12. Slaughter JC, Hardman JM, Kempe LG, Earle KM. Neurocutaneous melanosis and leptomeningeal melanomatosis in children. Arch Pathol 1969;88:298–304. 13. Reyes-Mugica M, Alvarez-Franco M, Bauer BS, Vicari FA. Nevus cells and special nevomelanocytic lesions in children. Pediatr Pathol 1994;14:1029–1041. 14. Zu´n˜iga S, Las Heras J, Benveniste S. Rhabdomyosarcoma arising in a congenital giant nevus associated with neurocutaneous melanosis in a neonate. J Pediatr Surg 1987;22: 1036–1038. 15. Schmitt FC, Bittencourt A, Mendonca N, Dorea M. Rhabdomyosarcoma in a congenital pigmented nevus. Pediatr Pathol 1992;12:93–98. 16. Bolande RP. Neurocristopathy: its growth and development in 20 years. Pediatr Pathol Lab Med 1997;17:1–25. 17. Roth MJ, Medeiros LJ, Kapur S, et al. Malignant schwannoma with melanocytic and neuroepithelial differentiation in an infant with congenital melanocytic nevus: a complex neurocristopathy. Hum Pathol 1993;24:1371– 1375. 18. Cohen MC, Kaschula ROC, Sinclair-Smith C, Emms M, Drut R. Pluripotential melanoblastoma, a unifying concept on malignancies arising in congenital melanocytic nevi: report of two cases. Pediatr Pathol Lab Med 1996;16:801– 812. 19. Banerjee SS, Menasce LP, Eyden BP, Brain AN. Malignant melanoma showing ganglioneuroblastic differentiation. Report of a unique case. Am J Surg Pathol 1999;23:582– 588.

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