Melanotic Neuroectodermal Tumor of Infancy

Background

Melanotic neuroectodermal tumor of infancy (MNTI) is a relatively uncommon osteolytic-pigmented neoplasm that primarily affects the jaws of newborn infants.^[1] The lesion has had an interesting history since its initial description by Krompecher in 1918 as a congenital melanocarcinoma.^[2]

For the next 5 decades, the lesion was reported under a variety of different names as succeeding authors attempted to identify the cell of origin. Some of the terms applied to this lesion included pigmented ameloblastoma, retinal anlage tumor, melanotic progonoma, melanotic adamantinoma, and pigmented epulis of infancy.^{[3, 4, 5]} These terms reflected theories of suspected origin from the odontogenic apparatus, the pigmented anlage of the retina, or the sensory neuroectodermal tissues.

In 1966, Borello and Gorlin reported a case with high urinary excretion of vanillylmandelic acid (VMA), suggesting a neural crest origin, and they proposed the term melanotic neuroectodermal tumor of infancy.^[6] Since then, numerous histochemical, immunohistochemical, electron microscopic, and tissue culture studies have supported the neural crest origin and confirmed the preferred term of melanotic neuroectodermal tumor of infancy.^{[7, 8, 9, 10]}

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Pathophysiology

Several patients with melanotic neuroectodermal tumor of infancy (MNTI) have demonstrated a high urinary excretion of VMA.^{[6, 11]} This finding adds credence to a neural crest origin because elevated VMA has been reported in neuroblastoma, ganglioneuroblastoma, pheochromocytoma,^[12] and other neural crest tumors. However, the presence of elevated urinary VMA is not diagnostic for MNTI.

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Epidemiology

Frequency

Melanotic neuroectodermal tumor of infancy (MNTI) is a rare neoplasm and approximately 485 cases have been reported in the literature to date worldwide.

Sex

Melanotic neuroectodermal tumor of infancy (MNTI) has a slight male predilection, with a male-to-female ratio of 1.3:1.^[13]

Age

Most patients, by some estimates more than 90%, present with the tumor in the first year of life, usually from age 1-6 months, with a peak between the second and sixth month of life.^[14] A few cases of melanotic neuroectodermal tumor of infancy (MNTI) have been reported in adults, notably, a 23-year-old man, a 39-year-old woman, and a 67-year-old woman.^{[15, 16, 17]} However, only 9% of cases are seen in patients older than 12 months.^[18]

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Prognosis

Most melanotic neuroectodermal tumors of infancy (MNTIs) are benign and effectively managed by aggressive surgical excision. Reconstruction may be challenging. In a systematic review, a recurrence rate of 20% was found, with the highest relative risk for recidivation being found in the mandible and skull (33.3% and 31.8%, respectively). Most recurrences appear to occur within 4 weeks after the operation. A comprehensive systematic review of 472 cases of MNTI found that age at diagnosis is an important prognostic indicator in these tumors. Infants diagnosed within the first 2 months of birth have a shorter disease-free survival period and the recurrence tends to occur within only 6 months from treatment, while patients older then 4.5 months have minimal risk of recurrence.^[13] Unfortunately, reports have shown that recurrent tumors tend to behave more aggressively and involve other anatomic structures such as the orbit and skull base.^{[19, 20]} Additionally, a malignancy rate of 6.5% has been reported for these tumors, with most malignant cases occurring in the skull and brain. Only very few tumors produce metastases and death.^[18]

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History

Although melanotic neuroectodermal tumor of infancy (MNTI) is classified as a benign lesion, it is often clinically worrisome because of its rapid onset and alarming local growth rate.^{[19, 21]} Often, sucking and feeding are impaired secondary to the swelling.^{[11, 22]} The patient usually is asymptomatic.

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Physical Examination

More than 90% of cases of melanotic neuroectodermal tumor of infancy (MNTI) occur in the head and neck region, with a striking predilection for the anterior portion of the maxilla. In fact, the maxillary bone is the location of approximately 61% of reported cases.^[18] Other less frequently affected sites include the skull (16%), the epididymis and testis (9%), the mandible (6%), and the brain (6%).^[18] A few cases have been reported in unusual locations such as the subcutaneous soft tissue of the thigh and forearm, the femur, the fibula, the mediastinum, the shoulder, and the uterus.^{[7, 23, 24, 25, 26]}

All but two of the reported cases in the literature have been solitary lesions.^{[27, 28]}

The typical MNTI begins as a nonulcerated, lightly pigmented, blue or black lesion on the anterior aspect of the maxilla and rapidly expands to form a swelling or tumescence (see the image below) that is cosmetically obvious to the parents of the infant.

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Melanotic neuroectodermal tumor of infancy presents as a rapidly growing bluish mass on the anterior aspect of the maxilla.

The intraoral lesion appears as a sessile, lobulated mass, often reaching 2-4 cm in diameter by the time of diagnosis. Bone destruction and displacement of teeth often occur because of the intraosseous location in the maxilla. No thrill or pulse can be elicited from the MNTI. Although the lesion expands rapidly, the overlying mucosa usually remains intact.

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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.

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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.

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The biphasic population of cells demonstrates alveolar structures lined by cuboidal epithelioid cells demonstrating granules of dark-brown melanin pig....

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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Surgical Care

The treatment of choice for melanotic neuroectodermal tumor of infancy (MNTI) is surgical excision, and it is usually curative.^{[11, 18, 44]}  Existing teeth and developing teeth must be sacrificed when they lie within the lesion or near the borders of an MNTI. Some controversy still exists regarding the amount of adjacent bone that needs to be removed during the surgical procedure. Many clinicians advocate for a 5-mm margin of healthy tissue be included with the surgical specimen.^{[45, 46]} Others advocate for only enucleation of the tumor followed by curettage of the bony cavity.^{[11, 47]}

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Adjuvant and Neoadjuvant Therapies

Complete tumor removal of the melanotic neuroectodermal tumor of infancy (MNTI) may not be the goal when it may sacrifice vital structures such as the orbital or intracranial contents. In such cases, adjuvant chemotherapy may be beneficial.^[48] Cases of primarily inoperable MNTIs have also been reported, for which chemotherapy was performed to reduce extension of the tumor mass before surgical treatment.^{[49, 50]} Only rarely has radiotherapy been successfully used in combination with surgical treatment or in combination with chemotherapy and surgical treatment for MNTI.^{[51, 52]}

Local recurrence is a possibility and has been documented to range from 10-60% of patients, depending on the study. Overall, recurrence has been reported to occur in 20% of cases.^[18] The recurrent lesions, possibly secondary to inadequate excision or multicentricity, usually become apparent within the first year after surgery. In instances of inoperable recurrence or when clear margins are impossible to obtain, chemotherapy and/or radiation therapy have been used.^{[20, 51, 52, 53]}

Neven et al in 2008 advocate for adjuvant chemotherapy in cases of multiple aggressive recurrences and/or inoperable tumors.^[19] These authors followed a successful neuroblastoma chemotherapy protocol for a recurring aggressive MNTI, which, in molecular studies, showed 1p deletion and gain of chromosome 7q, analogous to a neuroblastoma. Hence, in cases in which chemotherapy is necessary, it appears that molecular studies of the resection specimen might be beneficial to identify which protocol will have the most successful results.

Interestingly, Davis et al in 2015 reported a unique mixed response of an aggressive recurrent tumor to neoadjuvant chemotherapy using agents known to be effective for neuroblastomalike tumors (vincristine and cyclophosphamide).^[20] The postchemotherapy surgical specimen showed that the treatment resulted in complete obliteration of the neuroblastlike cells, but only a minimal effect in reducing the larger, polygonal cell population.

Gomes et al in 2015 found a BRAFV600E oncogenic mutation in one case of MNTI of the three studied. This might suggest that currently available BRAF-targeted therapies might be successful alternative treatments for aggressive MNTIs harboring the mutation.^[54]

A 2016 study performed exhaustive genomic, transcriptomic, epigenetic, and pathological characterization of a MNTI involving the fibula of a 2-month-old baby girl. Whole-exome analysis of genomic DNA from both the tumor and blood indicated a heterozygous, unique-germline, loss-of-function mutation in CDKN2A (p16^INK4A , D74A), as well as tumor-promoting somatic fusion genes and epigenetic deregulation. The study also found that a derived MNTI cell line was sensitive to inhibitors of lysine demethylase.^[26]

Although MNTI is an aggressive benign tumor, malignant variants have been reported. Of reported cases, mostly of the brain and skull, 6.5% have exhibited malignant behavior.^[18] Nevertheless, some authors believe the estimation of 6.5% is probably exaggerated in the literature because unusual malignant cases are more likely to be reported.^{[1, 22]} Metastatic spread of MNTI occurs infrequently, in less than 5% of malignant cases. Management of these rare cases is different. Few, if any, parameters exist, either clinically or histologically, to predict the development of metastatic lesions.^[34] In a few cases reported as malignant, the histologic features have taken on a neuroblastomalike appearance.^{[9, 37]}

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Long-Term Monitoring

Address the documented 20% recurrence rate of melanotic neuroectodermal tumor of infancy (MNTI) in the postoperative care by monitoring the patient with physical and radiographic examination at monthly intervals for the first two postoperative years. Moreover, an estimated malignant transformation rate of 6.5% highlights the possibly serious nature of this tumor and the need for careful clinical evaluation and close follow-up of affected patients, especially for tumors located in the brain and skull.

Permanent reconstruction of the maxillary alveolus and missing dentition may have to be delayed until after growth is completed, often in the teenage years. In the interim, transitional removable partial dentures may be necessary. The skills of an orthodontist, prosthodontist, oral surgeon, and/or dentist may be required, based on the extent of the missing structures, to correct any functional and cosmetic deformity.

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