Melanotic Neuroectodermal Tumor of Infancy Workup

Updated: Jun 19, 2018
  • Author: Leticia Ferreira, DDS, MS; Chief Editor: William D James, MD  more...
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Workup

Laboratory Studies

Typically, the hematologic laboratory values and 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 vanillylmandelic acid (VMA). [6] Elevated VMA has been reported in other tumors of neural crest origin, such as pheochromocytoma, ganglioneuroblastoma, retinoblastoma, and neuroblastoma. The urinary level of VMA may return to the reference range after surgical removal of an MNTI that has caused elevated VMA. [1] Additionally, no correlation between the presence of elevated VMA and more aggressive or malignant clinical behavior has been shown.

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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).

Conventional radiographs of MNTI within bone usually show a well-circumscribed or a diffuse, ill-defined radiolucency with bony expansion. [18] The bone is destroyed as the tumor advances, suggesting a malignant process. Although a few cases have been described as multiloculated, most MNTIs are unilocular. In its typical premaxillary position, the tumor can displace the developing deciduous and permanent dentition. Occasionally, an osteogenic reaction in the form of a faint spiculated or “sunburst” appearance may be seen that can be mistaken for an osteosarcoma. [1] These characteristics are noted best on maxillary occlusal, sinus, or periapical images of the involved area.

CT scanning defines the extent of the lesion, clearly delineates osseous involvement, and provides a good basis for surgical planning. Maxillary lesions usually demonstrate the radiolucent bony lesion causing bony expansion, sometimes with “free-floating teeth”. [29] Calvarial lesions may show spiculation and hyperostosis and the adjacent bones can be thickened as a result of reactive sclerosis. [30]

See the image below.

Axial CT, bone window, noncontrasted scan demonstr Axial CT, bone window, noncontrasted scan demonstrates expansile lytic lesion of the left maxilla producing displacement of dental follicles.

Additionally, MRI with gadolinium contrast can be used to evaluate the bony extent of the lesion. Most maxillary and calvarial MNTIs appear isointense or hypointense on T1-weighted images and hypointense on T-2 weighted images [29, 30] ; however, for the few MNTIs that contain a large amount of melanin, a higher signal intensity often occurs. [31, 32, 33] MNTIs may contain areas of reduced signal on both T1- and T2-weighted images, corresponding to areas of calcification, or in tumor lying near hyperostotic bone. [30] At no time are flow voids suggestive of a central hemangioma.

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Procedures

Upon completion of the clinical examination of the patient and 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.

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Histologic Findings

Grossly, the specimen has a gray, hard, rubbery consistency with foci of blue-black pigmentation. [34] Additionally, entrapped developing tooth buds may be noted in the specimen as the melanotic neuroectodermal tumor of infancy (MNTI) grows in and around the odontogenic apparatus.

The tumor cells form nests, tubules, or alveolarlike structures within a dense, collagenous, fibrous stroma. [1] 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.

The histologic appearance of an MNTI is unique and characteristic in that a distinct biphasic pattern exists, as shown in the image below. The first cell population consists of large, polygonal, epithelioid cells, which appear as islands or as forming tubular 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. [1, 35] Fontana stain can be used to enhance the demonstration of the melanin pigment.

The biphasic population of cells demonstrates alve The biphasic population of cells demonstrates alveolar structures lined by cuboidal epithelioid cells demonstrating granules of dark-brown melanin pigment. The second cell type is neuroblastic in appearance and consists of small, round, hyperchromatic cells.

The larger polygonal cells are at the periphery of the alveolar spaces, while the central portion contains the second smaller characteristic cell type. These cells are lymphocyte-like or neuroblastlike with small, dark nuclei and little, if any, cytoplasm. These cells occasionally also form isolated loose clusters of their own within the fibrous stroma. [1] 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. [36] The malignant diagnosis is more one of increased growth rate, infiltration, and metastases. Metastatic lesions have been described in lymph nodes, the liver, the pleura, bone marrow, soft tissues, and the pelvis. [9, 37, 38]

Immunohistochemistry is helpful in cases that are more difficult to diagnose. The larger polygonal cells express cytokeratins 8 and 18, protein gene product (PGP) 9.5, neuron-specific enolase, and melanoma-associated antigen ([human melanoma black [HMB]–45) and they are usually negative for S-100. The small, neuroblastlike cells express CD56, neuron-specific enolase and, in a few cases, PGP 9.5 and synaptophysin. [34, 39, 40] An uncommon CD99 expression in the large epithelioid cells has been reported in two clinically aggressive tumors. [24, 39] However, the prognostic significance of CD99 expression in MNTIs has yet to be further investigated.

A study analyzing cell-cycle regulatory proteins in MNTI found that MDM-2 protein, the product of a proto-oncogene that inhibits the regulatory function of the p53 protein, was expressed by the larger cells. The same researchers have also found greater expression of cyclin D1 and other cell-cycle regulatory proteins, such as cyclin A and proliferating cell nuclear antigen in the larger cells, suggesting that these cells are the more proliferative element of the tumor. [41]

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. [7, 8, 10, 40]

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, expression of melanotransferrin messenger RNA transcripts within the tumor was observed using a reverse transcriptase-polymerase reaction method, further confirming the neural crest origin of the tumor cells. [9, 42] The other small, dark, neuroblastlike cells have also been studied and although one case of MNTI has been reported to show chromosomal abnormalities analogous to neuroblastoma, [19] another earlier molecular genetic study found no genetic basis to link MNTI to neuroblastoma. [43] Accordingly, further molecular studies appear warranted in order to better elucidate the relationship between these two tumors.

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