Management of Melanotic Neuroectodermal Tumor of Infancy

Management of Melanotic NeuroectodermalTumor of InfancyMárcia Gaiger De Oliveira, DDS, Lester D.R. Thompson, MD,Anna Cecília Moraes Chaves, DDS, Pantelis Varvaki Rados, DDS,Isabel da Silva Lauxen, Biol, and Manoel Sant’Ana Filho, DDSMelanotic neuroectodermal tumor of infancy is a rare congenital neoplasm involvingthe head and neck in young patients. The clinical assessment, histologic diagnosis,and management is reviewed, with an emphasis on different treatment alternativesin two new case reports.Ann Diagn Pathol 8: 207-212, 2004. © 2004 Elsevier Inc. All rights reserved.Index Words: Melanotic neuroectodermal tumor of infancy, clinical, pathology,prognosis, differential diagnosisFrom the School of Dentistry, Oral Pathology, Universidade Federal doRio Grande do Sul, Porto Alegre, Brazil; and Southern CaliforniaPermanente Medical Group, Woodland Hills, CA.Address reprint requests to Lester D. R. Thompson, MD, SouthernCalifornia Permanente Medical Group, Department of Pathology, 5601De Soto Ave, Woodland Hills, CA 91367.© 2004 Elsevier Inc. All rights reserved.1092-9134/04/0804-0003$30.00/0doi:10.1053/j.anndiagpath.2004.04.003MELANOTIC neuroectodermal tumor of infancy(MNTI) is a rare, usually benign neoplasmof neural crest origin composed of relativelyprimitive pigment-producing cells. MNTI usuallyarises in infants within the first 6 months of life.Because of the uncommon occurrence of this neoplasm,past terms used to describe the tumor include“pigmented epulis,” “retinal anlage tumor,”“congenital melanocarcinoma,” “melanotic epithelialodontoma,” “melanotic ameloblastoma,” and“melanotic progonoma,” to name just a few. Itusually arises in the head and neck region andpredominantly affects the maxilla, 1-3 althoughother sites, such as brain, epididymis, mediastinum,femur, and ovary have also been reported. 2,4-10The tumor is usually nonulcerated and presentsas a soft tissue swelling, frequently affecting bone.Although the tumor cells produce melanin, pigmentationmay not be clinically evident. 2,4,9,10MNTI is a benign tumor, but can be locally aggressive,growing rapidly and resulting in tooth displacementas tumor cells invade bone. 1,11-13 Withplain radiographs, MNTI appear as intrabony expansiveareas of radiolucency, usually with poorlydemarcated margins, probably as a result of rapidtumor growth and a tendency to be locally invasive.Extensive tumor calcification may be identified. 5Teeth are usually displaced and appear within theradiolucent area of the tumor. 8,9 Computed tomography(CT) scans provide important informationregarding the extent of the lesion, thereby assistingin the development of a surgical plan. 9We report the clinical and histopathologic featuresof two cases of MNTI treated surgically, withand without incisional biopsy.Case 1Case ReportsA small mass was noted within the maxilla of amale patient at birth, with associated feeding problemsdeveloping during the ensuing 2 months.During this time the mass started growing rapidly,resulting in a referral at 2 months to the School ofDentistry, Universidade Federal do Rio Grande doSul (Porto Alegre, Brazil). No other physical, clinical,or laboratory abnormalities were identified,and there were no congenital anomalies. Clinicalexamination revealed a fluctuant blue mass coveredby an intact mucosa with expansion of the leftmaxillary alveolar ridge (Fig 1). Radiographic examinationrevealed a poorly defined osteolytic radiolucencyassociated with a left upper deciduouscentral incisor that was displaced anteriorly. CTshowed a radiolucent lesion with expansion of theAnnals of Diagnostic Pathology, Vol 8, No 4 (August), 2004: pp 207-212207

208 Gaiger de Oliveira et alFigure 1. Expansion of the left maxillaryalveolar ridge by a slightly “bluepurple”mass with intact overlying mucosa.surrounding bone in the area of the deciduouscentral incisor (Fig 2).An incisional biopsy performed under local anesthesiawas inconclusive, leading the surgeon toobtain diagnostic material under general anesthesia.Upon receiving a diagnosis of a MNTI, a secondFigure 2. Computed tomographyscan showing a radiolucent lesionwith expansion of the surroundingbone in the area of the deciduouscentral incisor. The macroscopicmass (inset) is well circumscribedand heavily pigmented.

Melanotic Neuroectodermal Tumor of Infancy209Figure 3. An intermediate power illustratingthe biphasic tumor cell population,with large and small cells.Crush artifact can sometimes obscurethe underlying tumor.operation was required to achieve complete surgicalextirpation. Postoperatively, a lumbar puncturewas negative for malignant cells, and there was noevidence of metastatic or disseminated disease. Thepatient is alive and well 7.5 years after the originalsurgery without disease and no recurrent tumor.Case 2A 3-month-old girl was referred for investigationof a swelling of the left maxillary alveolus. Thelesion was first noted at birth, but started growingrapidly 8 weeks before the visit, causing difficultieswith feeding. Clinical examination revealed an expansionof the left maxillary alveolar ridge by adarkly pigmented sessile mass with intact overlyingmucosa. There were no other clinical or physicalfindings of significance. CT scan showed a radiolucentlesion expanding the surrounding bone, andconfirmed the displacement of the left and rightupper deciduous central incisor and the left upperdeciduous lateral incisor.Surgical excision was performed under generalanesthesia, with curettage of the bone. The tumorwas well demarcated. The crown of a deciduoustooth was attached to the enucleated specimen.The patient had an uneventful postoperativecourse and is alive and well without evidence ofdisease or recurrence 4 years after the initial presentation.Pathologic FindingsMacroscopically, both intact lesions had a darkblue tinctorial surface, with sectioning through thehard mass revealing a mottled white-grey and darkblue cut surface (Fig 2, inset). The tumors were 4cm in greatest dimension.Microscopically, both tumors were remarkablysimilar, displaying a densely sclerotic fibrous connectivetissue stroma separating a biphasic neoplasticproliferation. A fibrous capsule was seen in bothcases, but the tumors were considered circumscribedrather than encapsulated. One populationwas composed of centrally located small, darklystained cells with hyperchromatic nuclei and scantcytoplasm. This population was usually surroundedby a second group of larger epithelioid cells thatcontained nuclei with vesicular nuclear chromatin(less chromatic than the smaller cells). These nucleiwere surrounded by more abundant cytoplasmcontaining melanin pigment, distributed in a heavygranular arrangement (Figs 3 and 4). The neoplasticcells were occasionally arranged in alveolar nests(Fig 4), small nests, and solid sheets. Necrosis,hemorrhage, nuclear atypia, and mitotic figureswere absent.DiscussionSeveral theories have been proposed to explainthe pathogenesis of this neoplasm which recapitu-

210 Gaiger de Oliveira et alFigure 4. High power with fibrousconnective tissue stroma separatinga nest of large, heavily melanin-pigmentedcells separated from smallcells with high nuclear to cytoplasmicratios and hyperchromatic nuclei.lates the early stages of retinal development (retinalanlage tumor). A congenital dysembryogeneticneoplasm arising from neural crest cells is theposited theory best supported by embryologic, ultrastructural,biochemical, immunohistochemical,electron microscopic, and molecular genetic studies.9,14,15 Support for this proposed neuroectodermalorigin is given with secretion of vanilmandelicacid or other catecholamines by the neoplasticcells, a finding characteristic of other tumors ofneural crest origin, such as pheochromocytoma,neuroblastoma, and ganglioneuroblastoma. 8 Aftertumor excision, vanilmandelic acid levels will usuallyreturn to normal. 2,10,11,16 Further support forthe neuroectodermal derivation is the expressionof melanotransferrin (a melanoma-specific peptidethat may play a role in iron metabolism) inMNTI. 15Tumors are circumscribed but not encapsulated.There is a biphasic tumor cell population arrangedin a background fibrous connective tissue stroma.The small, darkly staining cells comprise the majorityof the cells and have a “neural” quality withscant, fibrillar cytoplasm surrounding round nucleiwith coarse and heavy nuclear chromatin deposition.Usually identified in a central location, these“neuroblastic-like” cells are surrounded by a secondpopulation of larger epithelioid cells. Thesecells have significantly greater amounts of opaquecytoplasm filled with melanin pigment granulessurrounding nuclei that contain a more vesicularnuclear chromatin. The melanin pigment can be sodense as to obscure the nucleus. By definition,mitotic figures are inconspicuous and these tumorslack necrosis and hemorrhage.Immunohistochemical studies have shown thatthe large epithelioid cells are variably positive forvimentin, cytokeratin, epithelial membrane antigen,neuron-specific enolase, glial fibrillary acidicprotein, synaptophysin, Leu 7, and HMB45. Thesmaller, hyperchromatic cells are positive for neuron-specificenolase, glial fibrillary acidic protein,and synaptophysin. 1,2,6,7,9,17 S-100 protein is usuallynonreactive, although rare cases may be focallyimmunoreactive. Whereas the neoplastic cells showpolyphenotypic expression with neural, melanocytic,and epithelial markers, no photoreceptor(retinol-binding protein) or myogenic differentiationis noted. Furthermore, alpha-fetoprotein andneurofilament are also nonreactive, 17 helping toseparate other primitive neuroectodermal tumorsfrom MNTI.By ultrastructural examination, the biphasic natureof the tumor cells is also confirmed, withdense-core, membrane-bound neurosecretory granules,neurofilaments, and cytoplasmic processesidentified in the small cell population and modifiedtight junctions, melanosomes at various stages

Melanotic Neuroectodermal Tumor of Infancy211of development, and a single cilium identified inthe epithelioid population. 6,17,18The differential diagnosis of MNTI is quitebroad, but must be separated from other pediatric“small round cell” neoplasms such as neuroblastoma,Ewing’s sarcoma, peripheral neuroepithelioma,rhabdomyosarcoma, peripheral primitiveneuroectodermal tumor, desmoplastic small roundcell tumor, malignant melanoma, and lymphoma.Histopathologically, the biphasic neoplastic populationand polyphenotypic immunohistochemicalexpression is quite distinctive and unique frommost of the other pediatric “small blue round cell”neoplasms. 2,19 MNTI may share a common histologicand immunophenotypic expression with cellularblue nevus, melanoma, neuroblastoma, andrhabdomyosarcoma, but MNTI does not expressdiffuse reactivity with S-100 protein, lacks othermarkers of neuroendocrine differentiation, andlacks myo-D1, myoglobin, myogenin, and musclespecificactin reactivity. Melanoma is distinctly rarein pediatric patients and even more so if the “mucosal”sites of development of MNTI are considered.Cellular blue nevus characteristically has aspindle cell population, the cytoplasm of which isfilled with pigment, while MNTI does not containspindle cells. Teratoma, especially immature types,may show isolated foci of MNTI, but these foci areof no prognostic significance. Curiously, eventhough there is a histologic similarity with neuroblastomaand other pediatric neoplasms, there isno genetic basis at present to link them. 7,20A limited review of the English literature (1990to 2003) confirms that most MNTI occur in themaxilla and oral cavity in pediatric patients, with90% occurring in infants 1 year of age. 2,20-23There is no gender predilection with patients usuallypresenting with a unilateral, nonulceratedmass, present since birth, frequently associatedwith recent rapid enlargement. Symptoms are usuallypresent for an average duration of about 2months. A radiolucent expansion of the bone withtooth displacement is noted on plain radiographs,while vascular enhancement will be appreciated onpostcontrast images. The extent of the lesion is bestdelineated with a CT.Given the typical clinical features of these tumorsin the oral cavity, we believe that complete surgicalexcision with negative margins can be performedwithout a prior biopsy. This approach avoids unnecessaryanesthetic risk and reduces manipulationof the lesion, because it has been reported that thetumor seems to grow faster at previous biopsysites. 8,12 Although a conservative approach, consistingof local excision and curettage, 7,21 has beenadopted for the management of MNTI, the extentof the surgical excision has been debated. 2,3,9,17Different authors have reported large blunt dissection,19 en bloc excision of the tumor with reconstructionof the defect with autogenous costochondralgraft, 13 the use of chemotherapy alone, 22 or inassociation with radiation therapy, or radiationtherapy alone. 8,18,22 However, the successful managementof the two patients reported herein suggeststhat aggressive or radical surgery may not benecessary. Given the pigmentation of the lesion, itis usually possible to visualize the tumor limits andenucleate it as a whole (see Fig 2, inset). This wouldavoid tumor fragmentation that may lead to recurrence.Unfortunately, the biological behavior of thisneoplasm cannot be predicted by gross or histologiccharacteristics, requiring close and carefulclinical follow-up. 2,10,17,23 Rates of local recurrenceup to 45% after conservative excision have beenreported. 2,12,13,17 Recurrent tumors seem to growmore aggressively, tend to have indistinct borders,and may show osteoid formation, suggesting thatthe surgical procedures may trigger reactive boneformation. 11,24 Some authors have demonstrated asignificant presurgical reduction of the “neuroblastic-like”component with chemotherapy. 22 Whenmetastasis develops (up to 7% of cases), 2,6,10,17,18,21it is the “neuroblastic-like” component that is regardedas the aggressive part of the neoplasm.These malignant MNTI develop widespread metastasisand cause death within a few months. Consequently,these tumors are histologic mimics of neuroblastomarather than MNTI. 7,9 In this setting,surgery with adjuvant radiation and/or chemotherapyis the usual treatment. The usefulness of DNAploidy by flow cytometry in predicting tumor behavioris controversial, although aneuploidy is associatedwith tumor recurrence. 17ConclusionMelanotic neuroectodermal tumor of infancy is awell-characterized biphasic neoplastic lesion thatoccurs in infancy and may be treated conservativelyby surgical excision without an incisional biopsy,thus avoiding further manipulation of the lesion.

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