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Melanotic Neuroectodermal Tumor of Infancy: Differential Diagnoses & Workup

Author: William M Carpenter, DDS, MS, Professor, Chairman, Department of Pathology and Medicine, University of the Pacific Arthur A Dugoni School of Dentistry
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Updated: Sep 1, 2009

Differential Diagnoses

Other Problems to Be Considered

Consider clinical, radiographic, laboratory, and histologic findings when establishing a proper differential diagnosis for melanotic neuroectodermal tumor of infancy (MNTI). The MNTI often presents as a fast-growing lesion, suggesting a clinical impression of infection or malignant neoplasm. The location in the anterior aspect of the maxilla is consistent with a number of odontogenic cysts and tumors; however, the odontogenic cysts (eg, periapical cyst, dentigerous cyst, odontogenic keratocyst, calcifying odontogenic cyst) occur in an older age group, teenaged through middle-aged adults. The same age differential is noted with respect to the more common odontogenic tumors (eg, ameloblastoma, odontoma, adenomatoid odontogenic tumor, calcifying epithelial odontogenic tumor, ameloblastic fibroma, odontogenic myxoma, odontogenic fibroma).

In addition to a diagnosis of MNTI, the young age of the patient as well as the maxillary location is also compatible with a clinical diagnosis of congenital epulis of the newborn. Many nonodontogenic tumors are possible in the jaws, including central giant cell granuloma, ossifying fibroma, fibrous dysplasia, hemangioma, arteriovenous malformation, craniopharyngioma, Langerhans cell histiocytosis, rhabdomyosarcoma, Ewing sarcoma, and lymphoma. However, only Langerhans cell histiocytosis, rhabdomyosarcoma, Ewing sarcoma, and lymphoma are common in young children.

The radiographic appearance of a maxillary alveolar low-density radiolucency, containing no evidence of calcification, is consistent with any of the odontogenic cysts or tumors. Additionally, many of the aforementioned nonodontogenic lesions may also present with a radiographic appearance similar to that of MNTI.

Once a differential diagnosis is established from the clinical and radiographic findings, histologic evaluation is necessary to determine the final diagnosis. The histologic appearance of MNTI is usually that of a small, dark, cell neoplasm suggestive of neuroblastoma, rhabdomyosarcoma, Ewing tumor, lymphoma, desmoplastic small round cell tumor, and peripheral primitive neuroectodermal tumor. Although the histologic appearance is characteristic, special immunohistochemical stains and electron microscopy may be necessary to make a definitive diagnosis.

Workup

Laboratory Studies

• Typically, the hematologic laboratory values as well as the blood chemistry values are within the reference range. The only noteworthy laboratory value documented in some but not all patients with melanotic neuroectodermal tumor of infancy (MNTI) is an increase in the urinary level of MVA. Elevated MVA has been reported in other tumors of neural crest origin, such as pheochromocytoma, ganglioneuroblastoma, retinoblastoma, and neuroblastoma. As is the case for these lesions, the urinary level of VMA returns to the reference range after surgical removal of a MNTI that has caused elevated VMA. Additionally, no correlation between the presence of elevated VMA and more aggressive or malignant clinical behavior has been shown.

Imaging Studies

• Plain dental radiography, CT scanning, and MRI have been used to evaluate the content and the extent of melanotic neuroectodermal tumor of infancy (MNTI).
  • The radiographic appearance of MNTI within bone is a well-circumscribed radiolucency, although diffuse, ill-defined examples have also been reported. The bone is destroyed as the tumor advances, suggesting a malignant process. Although a few cases have been described as multiloculated, most MNTI are unilocular. In its typical premaxillary position, the tumor can displace or destroy the developing deciduous and permanent dentition. The MNTI that occurs predominantly within the marrow spaces of the maxilla and, on plain radiographs, appears as an irregular radiolucency. These characteristics are noted best on maxillary occlusal, sinus views, or periapical images of the involved area.
  • CT scanning with intravenous contrast is often used to delineate the margins of osseous involvement.

• Additionally, MRI with gadolinium contrast can be used to evaluate the bony extent of the lesion. Most MNTI appear as typical soft tissue tumors with nonenhancing heterogeneous tissue density; however, on T1-weighted MRI, for the few MNTI that contain a large amount of melanin, a higher signal intensity often occurs. At no times are flow voids suggestive of a central hemangioma.

Procedures

• Upon completion of the clinical examination of the patient as well as the imaging studies and urinalysis, the definitive diagnosis of melanotic neuroectodermal tumor of infancy (MNTI) is based on the histologic evaluation of a surgical specimen. Grossly, the specimen has a gray, hard, rubbery consistency with foci of blue-black pigmentation. Additionally, entrapped developing tooth buds may be noted in the specimen as MNTI grows in and around the odontogenic apparatus.

Histologic Findings

The histologic appearance of MNTI is unique and characteristic in that a distinct biphasic pattern exists. A moderately vascular fibrous background supports the MNTI. The peripheral borders are faintly noted, at best, by a thin, delicate, fibrous layer; however, most often, this nonencapsulated tumor shows local infiltration into the adjacent bone.

One portion of the lesion contains large polygonal cells arranged in sheets or alveolarlike structures. These large cells appear, under hematoxylin and eosin staining, to have pale abundant cytoplasm and pale nuclei with finely dispersed chromatin. These cells often contain the melanin pigment that gives the MNTI its blue-black clinical appearance.

Fontana stain can be used to enhance the demonstration of the melanin pigment. The cuboidal polygonal cells are at the periphery of the alveolar spaces, while the central portion contains the second smaller characteristic cell type. These cells are lymphocytelike or neuroblastlike with small, dark nuclei and little, if any, cytoplasm. These cells occasionally also form isolated clusters of their own within the fibrous stroma. Throughout the lesion, mitoses are rare but, when present, are normal in appearance. Cellular pleomorphism is scant. The few reported malignant cases of MNTI have little variation from the description above other than an increase in mitoses (3 or more per high-power field), hypercellularity, and focal necrosis.⁵ The malignant diagnosis is more one of increased growth rate, infiltration, and metastases. Metastatic lesions have been described in the lymph nodes, the liver, the adrenal gland, the spinal cord, and a variety of other sites.

Immunohistochemistry is of assistance in cases that are more difficult to diagnose. The cuboidal cells express cytokeratin as well as melanoma-associated antigen (HMB-45), but they are usually negative for S-100. Some cells are also positive for vimentin, epithelial membrane antigen, glial fibrillary acidic protein, neuron specific enolase (NSE), and synaptophysin.

Electron microscopic examination demonstrates ultrastructural evidence of neural, epithelial, and melanocytic features. Fine, delicate cytoplasmic fibers are suggestive of neurofibrils, reminiscent of glial tissue. Typically, some of the cells demonstrate neurosecretory granules. Evidence exists of basal laminae and interdigitating desmosomal attachments to adjacent cells, which is suggestive of epithelial features in some cells. Finally, melanosomes are noted in many of the cuboidal cells.

The polygonal cells noted for their melanin production have been cultured in vitro. These cells developed long dendritic processes suggestive of their neural crest origin. Additionally, melanotransferrin expression has been noted with DNA analysis of these cells. The other small, dark, neuroblastlike cells have also been studied; however, to date, no molecular genetic basis to link MNTI to neuroblastoma is apparent.

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