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Melanotic neuroectodermal tumour of infancy: Report of two cases and review of the literature
Journal of Cranio-Maxillo-Facial Surgery 40 (2012) e103ee107
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Case report
Melanotic neuroectodermal tumour of infancy: Report of two cases and review of the literature Spomenka Manojlovi c a, d, *, Miso Virag b, c, Ivica Luksi c b, c, Danko Müller d Institute of Pathology, University of Zagreb, School of Medicine (Chair and Head: Prof. Dr. Sven Seiwerth), Salata 10, 10000 Zagreb, Croatia Department of Maxillofacial Surgery, University of Zagreb, School of Medicine, Croatia c School of Dental Medicine, University Hospital Dubrava, Zagreb, Croatia d Department of Pathology, University Hospital Dubrava, Zagreb, Croatia a
b
a r t i c l e i n f o
a b s t r a c t
Article history: Paper received 10 March 2011 Accepted 25 May 2011
Melanotic neuroectodermal tumour of infancy (MNTI) is an uncommon tumour affecting predominantly the craniofacial bones of the newborn infants. The neural crest origin of the tumour has been confirmed. MNTI is generally accepted as a benign tumour despite of its rapid and locally infiltrative growth. Recurrence rate varies between 10% and 60%, and malignant behaviour has been reported in 6.5% of MNTIs. Systematic review of the literature revealed 445 MNTIs published between 1918 and 2010. We present additional two cases of MNTI from our Department, typical in all terms, which equals a total number of 447 reported cases. One of our cases revealed histological features consistent with malignant behaviour, but at present, 18 months after the surgical excision, there is no evidence of recurrence. Biological behaviour of MNTI cannot be predicted by gross or histologic characteristics, thus early diagnosis and careful follow-up after the complete surgical excision is required. Ó 2011 European Association for Cranio-Maxillo-Facial Surgery.
Keywords: Melanotic neuroectodermal tumour of infancy (MNTI) Jaw neoplasm
1. Introduction Melanotic neuroectodermal tumour of infancy (MNTI) is an uncommon, rapidly growing neoplasm of neural crest origin that primarily develops in the jaws of infants. The lesion was originally described by Krompecher in 1918, as a congenital melanocarcinoma. This tumour usually appears in infants during their first year of life in approximately equal sex distribution. In more than 90% of MNTIs, craniofacial sites are involved, including the maxilla which is the main site of origin (Cutler et al., 1981; Johnson et al., 1983; Dashti et al., 1999; Hoshina et al., 2000; Franchi et al., 2002; Wenig et al., 2005; Matsumoto et al., 2005; Karkuzhali et al., 2005; Koral et al., 2010). MNTI occasionally occurs in other sites (Schultz, 1957; Hameed and Burslem, 1970; D’Abrera and Burfitt-Williams, 1973; Desai et al., 2005; Elli et al., 2006; Lacy and Kuhar, 2010) and sometimes as a multilocular lesion (Steinberg et al., 1988; Hoshina et al., 2000; Choi et al., 2010). Despite of its rapid and locally destructive growth, MNTI is generally accepted as a benign tumour. The recurrence rate is rather
* Corresponding author. Department of Pathology, University Hospital Dubrava, ska 6, 10000 Zagreb, Croatia. Tel.: þ385 1 2902740; fax: þ385 1 2903141. Av. G. Su E-mail address: [email protected] (S. Manojlovi c).
high, varying between 10% and 60%. Malignant behaviour has been reported in 6.5% of MNTIs (Kruse-Lösler et al., 2006). 2. Case reports Only two cases of characteristic, rapidly growing MNTIs involving the maxillary region of newborn infants were seen in our Department during the last 30 years. 2.1. Case 1 A 3.5-month-old male infant was referred to the Department of Maxillofacial Surgery in March 1985 for the treatment of a progressive swelling of the hard palate. An odontogenic tumour has been diagnosed in another institution and enucleation of a maxillary mass was performed. A diagnosis of MNTI was made. On physical examination there was a scar from previous surgery as well as obvious eye protrusion on the right side. Intra-orally there was a swelling of the hard palate. Preoperative radiographs and CT scans demonstrated a maxillary tumour involving the posterior part of the maxilla and extending into the orbit. An extended maxillectomy and ethmoidectomy involving the pterygoid plates and the orbital contents were performed.
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The gross specimen comprised an irregularly shaped right maxilla. The cut surface revealed the maxillary sinus completely occupied by a firm, well-delineated mass, measuring 4.5e5 cm in diameter, protruding through the hard palate. The central portions of the tumour were hard, and peripheral parts were soft and greyish in colour with black pigmentation. Microscopically, the tumour was composed of a firm fibrous tissue with alveolar nests of the dual population of cells. The majority of tumour cells were small, round and uniform with hyperchromatic nuclei and inconspicuous cytoplasm. The other population of cells was larger, cuboidal with pale nuclei and abundant cytoplasm containing brown granules of melanin pigment (Fig. 1), arranged in gland-like structures surrounding the nests of small cells. Nuclear atypia, necrosis and mitotic figures were absent. The central portion of the tumour was composed of large amounts of woven bone trabeculae. Immunohistochemical analysis was not performed at that time. The patient has been followed-up for 26 years (to the present) and no recurrence of the tumour has been seen.
Fig. 1. Nests of small neuroblast like cells surrounded by a large, melanin containing cells, within a dense, well-vascularized fibrous stroma. H&E 100.
2.2. Case 2 The parents of a 6-week-old female infant noted a rapidly growing mass in the upper oral vestibule, 10 days prior to admission, in September 2009. Intra-oral examination revealed a well demarcated, rubbery mass, measuring 3 cm in diameter, in the anterior maxillary alveolar ridge, covered by mostly intact mucosa with dark brown discoloration, and a tooth bud protruding at the surface (Fig. 2). Other physical and laboratory findings were within normal limits. Computed tomography (CT) demonstrated an expansile lytic lesion of the right maxilla with displacement of dental follicles (Fig. 3). A partial maxillectomy involving the alveolar ridge, a part of the palate and the anterior wall was carried out. The surgical specimen was a part of the maxilla with a wellcircumscribed, firm tumour measuring 3.5 3.5 3 cm. The adjacent resection margin showed bone. The overlying mucosa was smooth, greyish with several dark spots and the tooth bud disclosed. Sectioning through tumour revealed a mottled white-gray and dark brownish surface of the tumour infiltrating the underlying bone. Microscopically, the tumour was composed of a moderately vascular fibrous stroma supporting the nests of the dual population of cells, in the same pattern as the tumour in Case 1. The only difference was the presence of frequent mitotic figures in Case 2 (5e10/10 high power fields), (Fig. 4). Immunohistochemical study was performed on the tumour tissue of both cases and the results were characteristic for MNTI and consistent with other reported MNTI immunoprofiles, as shown in Table 1. The expression of all markers analysed was practically identical in both cases, except for high Ki-67 positive fraction in Case 2 (Fig. 5). 3. Discussion Melanotic neuroectodermal tumour of infancy is a rare but clinically and histologically characteristic neoplasm of newborn babies. Since the first description by Krompecher (Krompecher, 1918) who called it congenital melanocarcinoma, several theories for the origin of this tumour have been proposed. Some investigators believed it arises from the retinal anlage, whereas others believed it to be of odontogenic origin (Clarke and Parsons, 1951; Kerr and Pullon, 1964; Dooling et al., 1977). A variety of terms including pigmented ameloblastoma, retinal anlage tumour, melanotic
Fig. 2. Well demarcated mass in maxillary anterior alveolar ridge, covered by mostly intact mucosa with dark brown discoloration and a tooth bud protruding at the surface.
progonoma, melanotic epithelial odontoma have been applied to this lesion. Borello and Gorlin (1966) reported a case with high urinary excretion of vanillylmandelic acid (VMA), suggesting a neural crest origin. They proposed the term as melanotic neuroectodermal tumour of infancy. The concept of neural crest origin had been confirmed by ultrastructural, immunohistochemical and tissue culture studies, and the term has been generally accepted. This tumour usually appears in infants during their first year of life, and 80% of patients are less than 6 months old. Several cases have been reported in older children and adults (Lurie, 1961; Jain et al., 2010). No predilection in sex has been noted, although some investigators have seen a tendency towards a higher prevalence in boys (Mirich et al., 1991; Pettinato et al., 1991; Kruse-Lösler
S. Manojlovic et al. / Journal of Cranio-Maxillo-Facial Surgery 40 (2012) e103ee107
Fig. 5. Nuclear expression immunoperoxidase 200. Fig. 3. Axial CT section demonstrates expansile lytic lesion of the right maxilla with displacement of dental follicles.
Fig. 4. High mitotic activity in Case 2. H&E 400.
Table 1 Immunohistochemical findings on tumour tissue of both cases. Case 1
Case 2
Large cells Small cells Large cells Small cells EMA þ Cytokeratin AE1/AE3 þ HMB 45 þþ S-100 Vimentin þþ NSE Synaptophysin Chromogranin A þ CD 56 þ CD 99 þ Bcl 2 Cyclin D1 þ Melan A, GFAP, AFP, p53, p21 Ki-67 <1%
þ þ þ þþ þþ <1%
þ þ þþ þþ þ þ þ þ þ <20%
þ þþ þþ þþ þþ >30%
All antibodies are mouse antihuman monoclonal antibodies manufactured by DakoCytomation, Copenhagen, Denmark. EMA (epithelial membrane antigen), NSE (neuron-specific enolase), GFAP (glial fibrillary acidic protein), AFP (a fetoprotein). þþ (diffuse and intensive positivity), þ (diffuse week positivity), (scattered cells positive), (negative reaction).
of
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et al., 2006; Barrett et al., 2002). In more than 90% of MNTIs, craniofacial sites are involved, with the maxilla as the main site of origin (68e80%), followed by the skull (10.8%), mandible (5.8%), and brain (4.3%) (Cutler et al., 1981; George et al., 1995; Liu et al., 2004). MNTI occasionally occurs in various other sites, such as mediastinum (D’Abrera and Burfitt-Williams, 1973), epididymis and testis (Desai et al., 2005), shoulder (Cutler et al., 1981), subcutaneous soft tissue of the thigh (Lacy and Kuhar, 2010), femur (Elli et al., 2006), ovary (Hameed and Burslem, 1970), and uterus (Schultz, 1957). Multilocular appearance has been documented (Steinberg et al., 1988; Choi et al., 2010). Recurrence rates of between 10% and 20% have been reported, but higher rates of between 40% and 60% have also been reported. Most of the recurrences after surgical treatment occurred within 4 weeks after the operation (Fowler et al., 2006; Kruse-Lösler et al., 2006). Malignant behaviour has been reported in five out of 158 cases of MNTI reviewed by Culter et al. (Cutler et al., 1981). The systematic literature review performed by Kruse-Lösler et al. (Kruse-Lösler et al., 2006) revealed a total of 23 malignant MNTIs of 355 cases reported in the period from 1918 to 2004, which gives a malignancy rate of 6.5%. Metastasis is rare (Dehner et al., 1979; Navas Palacios, 1980; Shokry et al., 1986; Jurincic-Winkler et al., 1994; Fowler et al., 2006). Clinically, MNTI appears as a painless, expansile, lobulated, partly pigmented tumour mass. Although well-delineated, it is usually an unencapsulated lesion that primarily affects the jaws of newborn children, frequently causing bone destruction and displacement of dental follicles. Except for the feeding difficulties, the infants are otherwise healthy. Physical and laboratory findings are usually within normal limits. In up to 44% of cases (Fowler et al., 2006) elevated levels of vanillylmandelic acid may be found, which normalize after the surgical therapy. The presence of plasma or urinary levels of VMA is neither diagnostic nor predictive. The imaging studies usually reveal a unilocular, well-circumscribed radiolucency expanding the underlying bone and entrapping developing tooth buds. Computed tomography (CT) scanning and magnetic resonance imaging can accurately define the extent of the lesion and thus provide a good basis for surgical planning. Magnetic resonance imaging shows an isointense mass on T1-weighted images, with focal areas of hyperdensity in lesions with large amount of intratumoural melanin. T2-weighted images show an isointense mass or decreased signal in melanotic tumours (Atkinson et al., 1989; Mirich et al., 1991; George et al., 1995). Microscopically, MNTIs are biphasic tumours, composed of small-cell and large-cell components arranged in nest-like or
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alveolar formations embedded within a well-vascularized fibrous stroma. The nests of small cells are usually surrounded by large cells forming gland-like structures and containing various amount of melanin granules in their cytoplasm. The immunohistochemical profile of MNTI is similar in all reported studies. The main characteristic cells are small cells of neural origin, confirmed by NSE, synaptophysin and chromogranin positivity, and large cells of ectodermal origin, confirmed by EMA, CK and HMB 45 positivity. S-100 protein is rarely positive and Melan A, GFAP and AFP are usually negative. Both cell types may express vimentin and CD 56. Use of expression of cell cycle-associated proteins (p53, proliferating cell nuclear antigen, cyclin D1, and cyclin A) in both neuroblastic and melanocytic cell populations does not seem clinically useful (De Souza et al., 1999), nor do flow cytometry ploidy findings (Kapadia et al., 1993). Barrett et al. (2002) in the analysis of eight cases of MNTI of the jaws noted a membrane expression of CD 99 and Ki-67 positive fraction of 25% in both cell populations in the most mitotically active lesion (7 mitoses/10 high power fields) and suggest that these features might indicate a more aggressive nature of the tumour, but this needed more rigorous investigation before conclusions could be drawn. Some authors (van Oijen et al., 1998) have shown that Ki-67 antigen may be present in noncycling cells as well, and therefore they advise against the use of Ki-67 to assess proliferative activity in tissues overexpressing p53 or p21. In our cases, the immunohistological features were similar to formerly published MNTIs. Tumour cells in Case 2 revealed mitotic activity of 5e10/10 high power fields, and proliferative activity of approximately 25% Ki-67 positive fraction in both cell components. Both, p53 and p21 were negative in our cases and the expression of CD 99 was similar in both cases. Both patients have been followed-up closely for 26 years and 1.5 year respectively, and there has been no evidence of recurrence to present. Heterologous tissue elements may also be found in MNTI (Slootweg, 1992). A differentiation pathway of the neural crest cells, destined to the dental lamina, under mesenchymal direction, could influence the tumour stroma morphogenesis: by a progressive transition from isolated fusiform cells within common fibroblasts to clusters of large pigmented cells (Kaya et al., 2000). In our Case 1 central portions of the tumour contained numerous woven bone trabeculae, confirming the potential of the neural crest cells to differentiate into various mesenchymal tissue types, suggested by Slootweg and documented also by other investigators (Hupp et al., 1981; Mirich et al., 1991; George et al., 1995; Hoshina et al., 2000). The differential diagnosis of MNTI involves inflammatory diseases (which can be ruled out by the lack of clinical and laboratory evidence of inflammation), clinically similar but histologically different congenital granular cell epulis, and odontogenic lesions that usually affect older children. The most important differential diagnostic problem is presented by malignant nonodontogenic paediatric “small round cell” neoplasms. These include neuroblastoma, Ewing’s sarcoma, rhabdomyosarcoma, desmoplastic small round cell tumour, malignant melanoma, peripheral primitive neuroectodermal tumour, and lymphoma (Gaiger de Oliveira et al., 2004), which express different immunohistochemical phenotypes. Molecular studies have failed to demonstrate a characteristic molecular overlap between MNTI and neuroblastoma, desmoplastic small round cell tumour, or primitive neuroectodermal tumour (Khoddami et al., 1998; Metwaly et al., 2005). MNTI generally follows a benign course. There are reports suggesting that even MNTIs showing histologically malignant features may do well (Damman et al., 1995; Barrett et al., 2002). Apart from one report of MNT of the brain recurring 12 years after complete remission (Omodaka et al., 2010), all other reported recurrences occurred during the first 18 months after the primary treatment (Matsumoto et al., 2005). Histological findings of a brisk mitotic
activity and marked proliferation index in our Case 2, strongly suggested malignant tumour. However, the patient has been followed-up for 18 months to date without any sign of. Radical surgical excision is the treatment of choice and curative in most cases. Although some authors reported a favourable outcome after surgical treatment and multimodal chemotherapy (De Chiara et al., 1992; Jurincic-Winkler et al., 1994; Mello et al., 2000; Shaia et al., 2002; Woessmann et al., 2003), in general, radiotherapy and chemotherapy have been shown to be ineffective in controlling MNTI (Johnson et al., 1983; Mirich et al., 1991; Damman et al., 1995; Dashti et al., 1999; Barrett et al., 2002). Surgical resection has been recommended for recurrent tumours as well (Atkinson et al., 1989; Dashti et al., 1999), and chemotherapy may serve as an alternative or adjuvant option in the treatment of widely extended MNTIs (Jenkinson et al., 1997; Woessmann et al., 2003). 4. Conclusion Melanotic neuroectodermal tumour of infancy, with its rapid clinical growth rate, could lead to the possibility of diagnosing MNTI as a malignant lesion with subsequent overtreatment. It has been considered as a benign neoplasm with high recurrence rate, and malignant cases developing widespread metastases and causing death within a few months have been documented. Despite all efforts to identify reliable prognostic indicators, at present there are no histological, immunophenotypical or molecular markers to predict the biological behaviour of this tumour in individual cases. The diagnosis of malignancy is more one of increased growth rate, infiltration, and metastases, thus early diagnosis and careful followup after the complete surgical excision is required. References Atkinson Jr GO, Davis PC, Patrick LE, Winn KJ, Ball TJ, Wylyn JB: Melanotic neuroectodermal tumor of infancy: MR findings and a review of the literature. Pediatr Radiol 20: 20e22, 1989 Barrett AW, Morgan M, Ramsay AD, Farthing PM, Newman L, Speight PM: A clinicopathologic and immunohistochemical analysis of melanotic neuroectodermal tumor of infancy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 93: 688e698, 2002 Borello ED, Gorlin RJ: Melanotic neuroectodermal tumor of infancy e a neoplasm of neural crest origin: report of a case associated with high urinary excretion of vanilmandelic acid. Cancer 19: 196e206, 1966 Choi BH, Park SW, Jang SM, Park BC, Son HN, Son JH, et al: Multicentric melanotic neuroectodermal tumor of infancy: a case report. J Korean Assoc Oral Maxillofac Surg 36(5): 434e437, 2010 Clarke BE, Parsons H: An embryological tumor of retinal anlage involving the skull. Cancer 4: 78e85, 1951 Cutler LS, Chaudhry AP, Topazian R: Melanotic neuroectodermal tumor of infancy: an ultrastructural study, literature review, and reevaluation. Cancer 48: 257e270, 1981 D’Abrera VS, Burfitt-Williams WA: Melanotic neuroectodermal neoplasm of the posterior mediastinum. J Pathol 111: 165e172, 1973 Damman O, Hagel C, Allers B, Grubel G, Schulte FJ: Malignant melanotic neuroectodermal tumor of infancy. Childs Nerv Syst 11(3): 186e188, 1995 Dashti SR, Cohen ML, Cohen AR: Role of radical surgery for intracranial melanotic neuroectodermal tumor of infancy: case report. Neurosurgery 45: 175e178, 1999 De Chiara A, Van Tornout JM, Hachitanda Y, Ortega JA, Shimada H: Melanotic neuroectodermal tumor of infancy. A case report of paratesticular primary with lymph node involvement. Am J Pediatr Hematol Oncol 14: 356e360, 1992 Dehner LP, Sibley RK, Sauk Jr JJ, Vickers RA, Nesbit ME, Leonard AS, et al: Malignant melanotic neuroectodermal tumor of infancy. A clinical, pathologic, ultrastructural and tissue culture study. Cancer 43: 1389e1410, 1979 Desai S, Roy S, Borges AM: Recurrent melanotic neuroectodermal tumour of infancy of the epididymis and testis: a case report. Indian J Pathol Microbiol 48(3): 363e364, 2005 De Souza PE, Merly F, Maia DM, Castro WH, Gomez RS: Cell cycle associated proteins in melanotic neuroectodermal tumor of infancy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 88: 466e468, 1999 Dooling EC, Chi JG, Gilles FH: Melanotic neuroectodermal tumor of infancy: its histological similarities to fetal pineal gland. Cancer 39: 1535e1541, 1977
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Case report
Melanotic neuroectodermal tumour of infancy: Report of two cases and review of the literature Spomenka Manojlovi c a, d, *, Miso Virag b, c, Ivica Luksi c b, c, Danko Müller d Institute of Pathology, University of Zagreb, School of Medicine (Chair and Head: Prof. Dr. Sven Seiwerth), Salata 10, 10000 Zagreb, Croatia Department of Maxillofacial Surgery, University of Zagreb, School of Medicine, Croatia c School of Dental Medicine, University Hospital Dubrava, Zagreb, Croatia d Department of Pathology, University Hospital Dubrava, Zagreb, Croatia a
b
a r t i c l e i n f o
a b s t r a c t
Article history: Paper received 10 March 2011 Accepted 25 May 2011
Melanotic neuroectodermal tumour of infancy (MNTI) is an uncommon tumour affecting predominantly the craniofacial bones of the newborn infants. The neural crest origin of the tumour has been confirmed. MNTI is generally accepted as a benign tumour despite of its rapid and locally infiltrative growth. Recurrence rate varies between 10% and 60%, and malignant behaviour has been reported in 6.5% of MNTIs. Systematic review of the literature revealed 445 MNTIs published between 1918 and 2010. We present additional two cases of MNTI from our Department, typical in all terms, which equals a total number of 447 reported cases. One of our cases revealed histological features consistent with malignant behaviour, but at present, 18 months after the surgical excision, there is no evidence of recurrence. Biological behaviour of MNTI cannot be predicted by gross or histologic characteristics, thus early diagnosis and careful follow-up after the complete surgical excision is required. Ó 2011 European Association for Cranio-Maxillo-Facial Surgery.
Keywords: Melanotic neuroectodermal tumour of infancy (MNTI) Jaw neoplasm
1. Introduction Melanotic neuroectodermal tumour of infancy (MNTI) is an uncommon, rapidly growing neoplasm of neural crest origin that primarily develops in the jaws of infants. The lesion was originally described by Krompecher in 1918, as a congenital melanocarcinoma. This tumour usually appears in infants during their first year of life in approximately equal sex distribution. In more than 90% of MNTIs, craniofacial sites are involved, including the maxilla which is the main site of origin (Cutler et al., 1981; Johnson et al., 1983; Dashti et al., 1999; Hoshina et al., 2000; Franchi et al., 2002; Wenig et al., 2005; Matsumoto et al., 2005; Karkuzhali et al., 2005; Koral et al., 2010). MNTI occasionally occurs in other sites (Schultz, 1957; Hameed and Burslem, 1970; D’Abrera and Burfitt-Williams, 1973; Desai et al., 2005; Elli et al., 2006; Lacy and Kuhar, 2010) and sometimes as a multilocular lesion (Steinberg et al., 1988; Hoshina et al., 2000; Choi et al., 2010). Despite of its rapid and locally destructive growth, MNTI is generally accepted as a benign tumour. The recurrence rate is rather
* Corresponding author. Department of Pathology, University Hospital Dubrava, ska 6, 10000 Zagreb, Croatia. Tel.: þ385 1 2902740; fax: þ385 1 2903141. Av. G. Su E-mail address: [email protected] (S. Manojlovi c).
high, varying between 10% and 60%. Malignant behaviour has been reported in 6.5% of MNTIs (Kruse-Lösler et al., 2006). 2. Case reports Only two cases of characteristic, rapidly growing MNTIs involving the maxillary region of newborn infants were seen in our Department during the last 30 years. 2.1. Case 1 A 3.5-month-old male infant was referred to the Department of Maxillofacial Surgery in March 1985 for the treatment of a progressive swelling of the hard palate. An odontogenic tumour has been diagnosed in another institution and enucleation of a maxillary mass was performed. A diagnosis of MNTI was made. On physical examination there was a scar from previous surgery as well as obvious eye protrusion on the right side. Intra-orally there was a swelling of the hard palate. Preoperative radiographs and CT scans demonstrated a maxillary tumour involving the posterior part of the maxilla and extending into the orbit. An extended maxillectomy and ethmoidectomy involving the pterygoid plates and the orbital contents were performed.
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The gross specimen comprised an irregularly shaped right maxilla. The cut surface revealed the maxillary sinus completely occupied by a firm, well-delineated mass, measuring 4.5e5 cm in diameter, protruding through the hard palate. The central portions of the tumour were hard, and peripheral parts were soft and greyish in colour with black pigmentation. Microscopically, the tumour was composed of a firm fibrous tissue with alveolar nests of the dual population of cells. The majority of tumour cells were small, round and uniform with hyperchromatic nuclei and inconspicuous cytoplasm. The other population of cells was larger, cuboidal with pale nuclei and abundant cytoplasm containing brown granules of melanin pigment (Fig. 1), arranged in gland-like structures surrounding the nests of small cells. Nuclear atypia, necrosis and mitotic figures were absent. The central portion of the tumour was composed of large amounts of woven bone trabeculae. Immunohistochemical analysis was not performed at that time. The patient has been followed-up for 26 years (to the present) and no recurrence of the tumour has been seen.
Fig. 1. Nests of small neuroblast like cells surrounded by a large, melanin containing cells, within a dense, well-vascularized fibrous stroma. H&E 100.
2.2. Case 2 The parents of a 6-week-old female infant noted a rapidly growing mass in the upper oral vestibule, 10 days prior to admission, in September 2009. Intra-oral examination revealed a well demarcated, rubbery mass, measuring 3 cm in diameter, in the anterior maxillary alveolar ridge, covered by mostly intact mucosa with dark brown discoloration, and a tooth bud protruding at the surface (Fig. 2). Other physical and laboratory findings were within normal limits. Computed tomography (CT) demonstrated an expansile lytic lesion of the right maxilla with displacement of dental follicles (Fig. 3). A partial maxillectomy involving the alveolar ridge, a part of the palate and the anterior wall was carried out. The surgical specimen was a part of the maxilla with a wellcircumscribed, firm tumour measuring 3.5 3.5 3 cm. The adjacent resection margin showed bone. The overlying mucosa was smooth, greyish with several dark spots and the tooth bud disclosed. Sectioning through tumour revealed a mottled white-gray and dark brownish surface of the tumour infiltrating the underlying bone. Microscopically, the tumour was composed of a moderately vascular fibrous stroma supporting the nests of the dual population of cells, in the same pattern as the tumour in Case 1. The only difference was the presence of frequent mitotic figures in Case 2 (5e10/10 high power fields), (Fig. 4). Immunohistochemical study was performed on the tumour tissue of both cases and the results were characteristic for MNTI and consistent with other reported MNTI immunoprofiles, as shown in Table 1. The expression of all markers analysed was practically identical in both cases, except for high Ki-67 positive fraction in Case 2 (Fig. 5). 3. Discussion Melanotic neuroectodermal tumour of infancy is a rare but clinically and histologically characteristic neoplasm of newborn babies. Since the first description by Krompecher (Krompecher, 1918) who called it congenital melanocarcinoma, several theories for the origin of this tumour have been proposed. Some investigators believed it arises from the retinal anlage, whereas others believed it to be of odontogenic origin (Clarke and Parsons, 1951; Kerr and Pullon, 1964; Dooling et al., 1977). A variety of terms including pigmented ameloblastoma, retinal anlage tumour, melanotic
Fig. 2. Well demarcated mass in maxillary anterior alveolar ridge, covered by mostly intact mucosa with dark brown discoloration and a tooth bud protruding at the surface.
progonoma, melanotic epithelial odontoma have been applied to this lesion. Borello and Gorlin (1966) reported a case with high urinary excretion of vanillylmandelic acid (VMA), suggesting a neural crest origin. They proposed the term as melanotic neuroectodermal tumour of infancy. The concept of neural crest origin had been confirmed by ultrastructural, immunohistochemical and tissue culture studies, and the term has been generally accepted. This tumour usually appears in infants during their first year of life, and 80% of patients are less than 6 months old. Several cases have been reported in older children and adults (Lurie, 1961; Jain et al., 2010). No predilection in sex has been noted, although some investigators have seen a tendency towards a higher prevalence in boys (Mirich et al., 1991; Pettinato et al., 1991; Kruse-Lösler
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Fig. 5. Nuclear expression immunoperoxidase 200. Fig. 3. Axial CT section demonstrates expansile lytic lesion of the right maxilla with displacement of dental follicles.
Fig. 4. High mitotic activity in Case 2. H&E 400.
Table 1 Immunohistochemical findings on tumour tissue of both cases. Case 1
Case 2
Large cells Small cells Large cells Small cells EMA þ Cytokeratin AE1/AE3 þ HMB 45 þþ S-100 Vimentin þþ NSE Synaptophysin Chromogranin A þ CD 56 þ CD 99 þ Bcl 2 Cyclin D1 þ Melan A, GFAP, AFP, p53, p21 Ki-67 <1%
þ þ þ þþ þþ <1%
þ þ þþ þþ þ þ þ þ þ <20%
þ þþ þþ þþ þþ >30%
All antibodies are mouse antihuman monoclonal antibodies manufactured by DakoCytomation, Copenhagen, Denmark. EMA (epithelial membrane antigen), NSE (neuron-specific enolase), GFAP (glial fibrillary acidic protein), AFP (a fetoprotein). þþ (diffuse and intensive positivity), þ (diffuse week positivity), (scattered cells positive), (negative reaction).
of
Ki.67
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et al., 2006; Barrett et al., 2002). In more than 90% of MNTIs, craniofacial sites are involved, with the maxilla as the main site of origin (68e80%), followed by the skull (10.8%), mandible (5.8%), and brain (4.3%) (Cutler et al., 1981; George et al., 1995; Liu et al., 2004). MNTI occasionally occurs in various other sites, such as mediastinum (D’Abrera and Burfitt-Williams, 1973), epididymis and testis (Desai et al., 2005), shoulder (Cutler et al., 1981), subcutaneous soft tissue of the thigh (Lacy and Kuhar, 2010), femur (Elli et al., 2006), ovary (Hameed and Burslem, 1970), and uterus (Schultz, 1957). Multilocular appearance has been documented (Steinberg et al., 1988; Choi et al., 2010). Recurrence rates of between 10% and 20% have been reported, but higher rates of between 40% and 60% have also been reported. Most of the recurrences after surgical treatment occurred within 4 weeks after the operation (Fowler et al., 2006; Kruse-Lösler et al., 2006). Malignant behaviour has been reported in five out of 158 cases of MNTI reviewed by Culter et al. (Cutler et al., 1981). The systematic literature review performed by Kruse-Lösler et al. (Kruse-Lösler et al., 2006) revealed a total of 23 malignant MNTIs of 355 cases reported in the period from 1918 to 2004, which gives a malignancy rate of 6.5%. Metastasis is rare (Dehner et al., 1979; Navas Palacios, 1980; Shokry et al., 1986; Jurincic-Winkler et al., 1994; Fowler et al., 2006). Clinically, MNTI appears as a painless, expansile, lobulated, partly pigmented tumour mass. Although well-delineated, it is usually an unencapsulated lesion that primarily affects the jaws of newborn children, frequently causing bone destruction and displacement of dental follicles. Except for the feeding difficulties, the infants are otherwise healthy. Physical and laboratory findings are usually within normal limits. In up to 44% of cases (Fowler et al., 2006) elevated levels of vanillylmandelic acid may be found, which normalize after the surgical therapy. The presence of plasma or urinary levels of VMA is neither diagnostic nor predictive. The imaging studies usually reveal a unilocular, well-circumscribed radiolucency expanding the underlying bone and entrapping developing tooth buds. Computed tomography (CT) scanning and magnetic resonance imaging can accurately define the extent of the lesion and thus provide a good basis for surgical planning. Magnetic resonance imaging shows an isointense mass on T1-weighted images, with focal areas of hyperdensity in lesions with large amount of intratumoural melanin. T2-weighted images show an isointense mass or decreased signal in melanotic tumours (Atkinson et al., 1989; Mirich et al., 1991; George et al., 1995). Microscopically, MNTIs are biphasic tumours, composed of small-cell and large-cell components arranged in nest-like or
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alveolar formations embedded within a well-vascularized fibrous stroma. The nests of small cells are usually surrounded by large cells forming gland-like structures and containing various amount of melanin granules in their cytoplasm. The immunohistochemical profile of MNTI is similar in all reported studies. The main characteristic cells are small cells of neural origin, confirmed by NSE, synaptophysin and chromogranin positivity, and large cells of ectodermal origin, confirmed by EMA, CK and HMB 45 positivity. S-100 protein is rarely positive and Melan A, GFAP and AFP are usually negative. Both cell types may express vimentin and CD 56. Use of expression of cell cycle-associated proteins (p53, proliferating cell nuclear antigen, cyclin D1, and cyclin A) in both neuroblastic and melanocytic cell populations does not seem clinically useful (De Souza et al., 1999), nor do flow cytometry ploidy findings (Kapadia et al., 1993). Barrett et al. (2002) in the analysis of eight cases of MNTI of the jaws noted a membrane expression of CD 99 and Ki-67 positive fraction of 25% in both cell populations in the most mitotically active lesion (7 mitoses/10 high power fields) and suggest that these features might indicate a more aggressive nature of the tumour, but this needed more rigorous investigation before conclusions could be drawn. Some authors (van Oijen et al., 1998) have shown that Ki-67 antigen may be present in noncycling cells as well, and therefore they advise against the use of Ki-67 to assess proliferative activity in tissues overexpressing p53 or p21. In our cases, the immunohistological features were similar to formerly published MNTIs. Tumour cells in Case 2 revealed mitotic activity of 5e10/10 high power fields, and proliferative activity of approximately 25% Ki-67 positive fraction in both cell components. Both, p53 and p21 were negative in our cases and the expression of CD 99 was similar in both cases. Both patients have been followed-up closely for 26 years and 1.5 year respectively, and there has been no evidence of recurrence to present. Heterologous tissue elements may also be found in MNTI (Slootweg, 1992). A differentiation pathway of the neural crest cells, destined to the dental lamina, under mesenchymal direction, could influence the tumour stroma morphogenesis: by a progressive transition from isolated fusiform cells within common fibroblasts to clusters of large pigmented cells (Kaya et al., 2000). In our Case 1 central portions of the tumour contained numerous woven bone trabeculae, confirming the potential of the neural crest cells to differentiate into various mesenchymal tissue types, suggested by Slootweg and documented also by other investigators (Hupp et al., 1981; Mirich et al., 1991; George et al., 1995; Hoshina et al., 2000). The differential diagnosis of MNTI involves inflammatory diseases (which can be ruled out by the lack of clinical and laboratory evidence of inflammation), clinically similar but histologically different congenital granular cell epulis, and odontogenic lesions that usually affect older children. The most important differential diagnostic problem is presented by malignant nonodontogenic paediatric “small round cell” neoplasms. These include neuroblastoma, Ewing’s sarcoma, rhabdomyosarcoma, desmoplastic small round cell tumour, malignant melanoma, peripheral primitive neuroectodermal tumour, and lymphoma (Gaiger de Oliveira et al., 2004), which express different immunohistochemical phenotypes. Molecular studies have failed to demonstrate a characteristic molecular overlap between MNTI and neuroblastoma, desmoplastic small round cell tumour, or primitive neuroectodermal tumour (Khoddami et al., 1998; Metwaly et al., 2005). MNTI generally follows a benign course. There are reports suggesting that even MNTIs showing histologically malignant features may do well (Damman et al., 1995; Barrett et al., 2002). Apart from one report of MNT of the brain recurring 12 years after complete remission (Omodaka et al., 2010), all other reported recurrences occurred during the first 18 months after the primary treatment (Matsumoto et al., 2005). Histological findings of a brisk mitotic
activity and marked proliferation index in our Case 2, strongly suggested malignant tumour. However, the patient has been followed-up for 18 months to date without any sign of. Radical surgical excision is the treatment of choice and curative in most cases. Although some authors reported a favourable outcome after surgical treatment and multimodal chemotherapy (De Chiara et al., 1992; Jurincic-Winkler et al., 1994; Mello et al., 2000; Shaia et al., 2002; Woessmann et al., 2003), in general, radiotherapy and chemotherapy have been shown to be ineffective in controlling MNTI (Johnson et al., 1983; Mirich et al., 1991; Damman et al., 1995; Dashti et al., 1999; Barrett et al., 2002). Surgical resection has been recommended for recurrent tumours as well (Atkinson et al., 1989; Dashti et al., 1999), and chemotherapy may serve as an alternative or adjuvant option in the treatment of widely extended MNTIs (Jenkinson et al., 1997; Woessmann et al., 2003). 4. Conclusion Melanotic neuroectodermal tumour of infancy, with its rapid clinical growth rate, could lead to the possibility of diagnosing MNTI as a malignant lesion with subsequent overtreatment. It has been considered as a benign neoplasm with high recurrence rate, and malignant cases developing widespread metastases and causing death within a few months have been documented. Despite all efforts to identify reliable prognostic indicators, at present there are no histological, immunophenotypical or molecular markers to predict the biological behaviour of this tumour in individual cases. The diagnosis of malignancy is more one of increased growth rate, infiltration, and metastases, thus early diagnosis and careful followup after the complete surgical excision is required. References Atkinson Jr GO, Davis PC, Patrick LE, Winn KJ, Ball TJ, Wylyn JB: Melanotic neuroectodermal tumor of infancy: MR findings and a review of the literature. Pediatr Radiol 20: 20e22, 1989 Barrett AW, Morgan M, Ramsay AD, Farthing PM, Newman L, Speight PM: A clinicopathologic and immunohistochemical analysis of melanotic neuroectodermal tumor of infancy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 93: 688e698, 2002 Borello ED, Gorlin RJ: Melanotic neuroectodermal tumor of infancy e a neoplasm of neural crest origin: report of a case associated with high urinary excretion of vanilmandelic acid. Cancer 19: 196e206, 1966 Choi BH, Park SW, Jang SM, Park BC, Son HN, Son JH, et al: Multicentric melanotic neuroectodermal tumor of infancy: a case report. J Korean Assoc Oral Maxillofac Surg 36(5): 434e437, 2010 Clarke BE, Parsons H: An embryological tumor of retinal anlage involving the skull. Cancer 4: 78e85, 1951 Cutler LS, Chaudhry AP, Topazian R: Melanotic neuroectodermal tumor of infancy: an ultrastructural study, literature review, and reevaluation. Cancer 48: 257e270, 1981 D’Abrera VS, Burfitt-Williams WA: Melanotic neuroectodermal neoplasm of the posterior mediastinum. J Pathol 111: 165e172, 1973 Damman O, Hagel C, Allers B, Grubel G, Schulte FJ: Malignant melanotic neuroectodermal tumor of infancy. Childs Nerv Syst 11(3): 186e188, 1995 Dashti SR, Cohen ML, Cohen AR: Role of radical surgery for intracranial melanotic neuroectodermal tumor of infancy: case report. Neurosurgery 45: 175e178, 1999 De Chiara A, Van Tornout JM, Hachitanda Y, Ortega JA, Shimada H: Melanotic neuroectodermal tumor of infancy. A case report of paratesticular primary with lymph node involvement. Am J Pediatr Hematol Oncol 14: 356e360, 1992 Dehner LP, Sibley RK, Sauk Jr JJ, Vickers RA, Nesbit ME, Leonard AS, et al: Malignant melanotic neuroectodermal tumor of infancy. A clinical, pathologic, ultrastructural and tissue culture study. Cancer 43: 1389e1410, 1979 Desai S, Roy S, Borges AM: Recurrent melanotic neuroectodermal tumour of infancy of the epididymis and testis: a case report. Indian J Pathol Microbiol 48(3): 363e364, 2005 De Souza PE, Merly F, Maia DM, Castro WH, Gomez RS: Cell cycle associated proteins in melanotic neuroectodermal tumor of infancy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 88: 466e468, 1999 Dooling EC, Chi JG, Gilles FH: Melanotic neuroectodermal tumor of infancy: its histological similarities to fetal pineal gland. Cancer 39: 1535e1541, 1977
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