Original Paper Pediatr Neurosurg 1992;18:6-15
A. Pierre-Kahna G. Cinallia A. Lellouch-Tubiana0 F. J. Villarejob C. Sainle-Rosea A. Pfisterc G. Coulyd
Melanotic Neuroectodermal Tumor of the Skull and Meninges in Infancy
a Neurosurgery, Hôpital des Enfants Malades, Paris. France; b Nacional Infantile Nino Jesus, Madrid. Spain; ° Histopathology Laboratory, and d Stomatology, Hôpital des Enfants Malades. Paris, France
Abstract
Three cases of melanotic neuroectodermal tumors of infancy are presented. Two were localized on the midline, involving the skull and extending subdurally. One was located on the inner aspect of the dura and developed intracranially. Two had a benign course following gross total removal. One had a malignant course, recurring locally and spreading within the brain. The diffi culties of removing these tumors when they are implanted on the midline are stressed. Histological features of prognostic value are pointed out. Further support for neural crest origin of these tumors is given.
Few tumors have been named so variously as the mela notic neuroectodermal tumor. The most common de nominations have been melanotic progonoma [1], mela notic adamantinoma [2], pigmented epulis [3], and retinal anlage tumor [4], Since 1986 the official denomination is melanotic neuroectodermal tumor of infancy (MNTI) be cause most of these lesions develop early in infancy [5, 6]. Localization of MNTI in the skull or the dura is rare, although second in frequency after the maxilla and man dible [7], Out of over 200 reported MNTI, only 26 involve the calvarium. Excellent reviews have been written about these tumors, from both clinical [7-13] and histopathological [7, 14-17] standpoints. Three reasons, however, lead us to publish 3 new cases of neurosurgical interest. First, the symptoms are frequently misleading and there fore the diagnosis and subsequent treatment can be inap propriate. This is probably due to the rarity of MNTI and hence the limited clinical experience. Second, both their
clinical presentation and prognosis may differ from their classical description. Third, these tumors, when located on the midline, may be difficult and dangerous to re move.
Clinical Presentation Observation No. I A 2-month-old Laotian female was hospitalized on December 7, 1983, for a small lump at the anterior fontanel. In a few days, the mass increased dramatically in size (fig. 1). When seen in the Hopital des Enfants Malades in Paris, the child presented with a huge, pain less. fixed mass covered with normal skin. Skull films revealed a tumor at the site of the bregma measuring 6 X 10 cm and involving the frontal and both parietal bones. The lesion was characterized by a zone of hyperostosis surrounded on both sides by a corona of bony spicules giving typical sunburst patterns. There was no evidence of lytic destruction. A noncontrasted computed tomography (CT) scan demonstrated a well-delimited, hyperdense. heterogeneous mass in-
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KeyWords Melanotic tumors Neurocranium Infants Neural crest
volving the bony calvarium at the bregma and extending intracranially down to the corpus callosum. Following intravenous contrast injection, there was bright enhancement of the lesion (fig. 2). On angiography, its feeding arteries were branches of the two external carotid arteries, mainly the temporal and the anterior meningeal. The tumor was biopsied. but it proved impossible to decide between neuroblastoma and MNTI. Urinary levels of homovanillic acid (F1VA) and of vanilmandelic acid (VMA) were normal. Chemother apy (cyclophosphamide, adriamvein) failed to reduce the size of the tumor preoperatively. On January 13. 1983, the tumor was excised in toto and ‘cn bloc' by circumferential craniectomy through apparently normal bone margins. The tumor had perforated the dura, being both extra- and subdural. Its surface was flecked by black pigment. It had a firm and gritty consistency. The end of the surgical procedure was complicated by sudden bleeding from the sagittal sinus. A brief car diac arrest ensued and the child required resuscitation. The dural and skull defects were repaired by means of a film of Dacron and acrylic cranioplasty, respectively. The definitive histopathological diagnosis of the tumor was typical MNTI. The margins of the cran iectomy were tumor free. No complementary postoperative treat ment was given. Further development of a fluid collection inside the operative cavity required the insertion of a subduroperitoneai shunt. Seven years postoperatively, the child was tumor free and ncurologicallv normal.
Fig. 2. Case 1: CT scan after injection. Frontal view. An enhanc ing tumor extends subcutaneously and intracranially from both side of a median and paramedian frontal hyperostosis. The subgaleal component of the lesion is small as compared with its intracranial component.
Observation No. 2
A painless but rapidly growing left frontal swelling was first noted in a 12-month-old Black male. One month later, the infant was trans ferred to our unit at the Hopital des Enfants Malades in Paris. In the meantime, he had stopped walking and had become irritable. Upon admission, the bump was considerably larger than reported a few weeks earlier. The mass was fixed to the ncurocranium but not to the overlying scalp. In addition, the patient had brisk reflexes at the 4 limbs and a macrocranium at + 5 SD. The ocular fundi, however, were normal. Xerographies of the skull show'cd the inner and outer tables of the left frontal bone to be the seat of both dense sclerosis and hyperostosis; spicules irradiating in all directions from this hyperos tosis produced a sunburst appearance. CT scan confirmed these aspects and revealed, in addition, the presence of a huge contralateral enhancing intracranial cystic mass, shifting the midline and the ven tricles from right to left. On magnetic resonance without injection the major part of the mass was slightly hypointense as compared to the brain on both the Ti and Ti relaxation times. However, a small com ponent of the lesion was hyperintense on T|- and hypointense on Ti-weightcd images (fig. 3). After injection (fig. 4). there was bright enhancement of the whole solid mass. Selective angiographies showed a slight tumoral blush from anterior branches of both the external and internal right carotid arteries. Given the angiographic features, a biopsy was surprisingly complicated by hemorrhage, necessitating a 400-ml transfusion. Histological diagnosis of the sam ples was in favor of MNTI. To reduce the volume of the lesion before removing the tumor.a Rickham reservoir was inserted inside the cyst (03/01/90). The liquid, withdrawn daily, contained a high level of
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Fig. 1. Case 1: Xerographies demonstrating the considerable increase in size of the tumor of the skull at 2-month interval. The lesion, located on the midline, involves each edge of the coronal sutures and develops both subcutaneously and extradurally. The presence of hyperostosis is responsible fora sunburst appearcnce.
Fig. 3. Case 2: Magnetic resonance imaging. Frontal views. Without injection, the tumor is isointense to the surrounding brain tissue on both the Tj-(a) and Ti-(b) weighted images, except for a small part of it (arrow) which is hyperintense in Ti and hypointense in T \ This behavior is characteristic of melanin-containing tumors.
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Fourteen months after the first operation, the child was operated on again for local recurrence. The metastasis were completely removed, a ventriculoperitoneal shunt was inserted and a course of chemotherapy was reinitiated postoperatively. Three months post operatively, CT scan showed numerous enhancing nodules wide spread on the inner aspect of the dura and filling the lumen of the sagittal sinus above the level of the torcular. These nodules were interpreted as resulting from tumoral seeding. Observation No. 3
A 3-year-old White female was hospitalized on October 3, 1983, in the neurosurgical department of the Hospital Nacional Infantil Nino Jesus in Madrid after a left focal seizure. Clinical examination was normal, particularly the shape of her skull. On standard X-rays, there was a round-shaped right pterional calcified mass (fig. 5). CT scan revealed an intracranial, heterogeneous and enhancing tumor, attached to a thickened and dense right pterion. The brain surround ing the tumor was hypodensc and edematous (fig. 6). As demon strated by right carotid angiography, the blood to the tumor was sup plied exclusively by anterior temporal branches of the external carot id. The child was operated on November 8, 1983. Intraoperatively, the vault was normal. The pterion was the seat of hyperostosis. The tumor, exclusively subdural, was firmly attached to the inner aspect of the dura covering the pterion, clearly delimited from the overlying brain. The tumor was removed in toto with its dural attachment. On the surface, it was diffusely darkly pigmented. No complementary postoperative treatment was given. Seven years later, the child was neurologically intact and free of disease.
Pierrc-Kahn/Cinalli/Lellouch-Tubiana/ Villarcjo/Saintc-Rose/Pfister/Couly
Melanotic Neuroectodermal Tumors
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HVA (3.57 nmol/1) and VMA (136 nmol/l). However, 24-hour urine determination of these metabolites was normal. After repeated punc tures of the cyst, the child recovered a normal neurological condition and was then operated on (03/19/90). Craniectomy, passing far from the tumor, was performed. It was unclear, however, whether the bone was normal at its margin. The tumor itself had perforated the dura and obliterated the superior sagittal sinus, making possible the section and the removal of this part of the sinus. The subdural com ponent of the lesion, including its cystic portion, was easily divided from the adjacent brain and removed apparently in toto. The solid part of the tumor was diffusely black. The dural defect was closed with a film of Dacron. The defect at the skull was repaired I month later using an irradiated bone graft. Meanw hile, external hydroceph alus developed in the operative field, necessitating insertion of a subduroperitoneal shunt. Recovery was uneventful, and the infant was discharged within 5 weeks, neurologically intact, and. as seen on the postoperative CT scan, free of tumor. He was. however, rehospital ized on August 3. 1990. for the onset of left hemiparesis. On a new CT scan there was not only a right frontal recurrence, but also two intracranial mctastascs on the left side. Chemotherapy was initiated using cyclophosphamide (100 mg/nWday for 3 days) and carboplatin (100 mg/nWday for 3 days), and then cyclophosphamide ( 150 mg/nWday for 3 days) and etoposide (1 g/nWday for 3 days). In 2 months the left paramedian metastasis had cleared up, while the local recurrence and the occipital metastasis had reduced signifi cantly in size. Six months postoperatively, the images were stable and the child was in excellent general condition w'ith slight left hemi paresis.
Fig. 4. Case 2: Preoperative magnetic resonance imaging. Para median sagittal view. Demonstration after contrast injection of a huge enhancing intracranial mass associated with a deep intracere bral cyst and a frontal hyperostosis (arrows).
Fig. 5. Plain radiogram of the skull. Sagittal view. Presence of a round-shaped calcified lesion surrounding a hyperostotic pterion.
Fig. 6. Case 3: CT scan after injection. Axial views. Presence of a calcified heteroge neous, enhancing intracranial tumor at tached to a thickened hyperdense pterion. Note that the external aspect of the calvar ium at this level is normal.
Gross Features
In observations 1 and 2. the gross features were simi lar: the growths involved the vault and had both a subdu ral and extradural component. The 3rd observation dif
fered from the first two in that the vault was not tumoral, the tumor being only subdural and firmly attached to the inner aspect of the dura. In all 3 cases, however, the bone close to the lesion was the seat of sclerosis and hyperosto sis. In all cases, the tumors were large, measuring 6-9 cm in diameter. Their outer surface was multinodular and
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Pathology
Fig. 7. Microphotograph showing two cell types: small rounded undifferentiated cells (thin arrows) with scant cytoplasm and large brown cells (thick arrows). HE. X 324. Fig. 8. Microphotograph at higher magnification showing the two cell types and the presence of melanic pigment in the large-cell cyto plasm. X 1,200. Fig. 9. Electron micrograph of large pigmented cells. The cyto plasm contains electron-dense granules in various stages of matura tion (*). Uranyl acetate. Lead citrate X 4.000.
Miicroscopic Findings
The tumors were virtually similar in the routine prepa rations. The most striking feature was the presence of two distinct cell populations in the tumor (fig. 7). The first was composed of small rounded undifferentiated cells with hyperchromatic nuclei and scant cytoplasm. They were of ncuroblastic type, and the cells were arranged in the form of irregular nests and cords. Neither neuronal differentia tion nor rosette formation was seen. The second cell pop ulation consisted of large cells with vesicular nuclei and eosinophilic cytoplasm, frequently containing fine granu lar melanic pigment (fig. 8). This pigment did not stain with the Prussian blue stain for iron but was strongly posi tive with the Fontana method for melanin. These large
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pigmented cells affected pseudoalveolar patterns dis persed within the stroma. This stroma was composed of hypocellular dense collagenous connective tissue. In the first two observations, the tumor invaded the surrounding bone. There was extensive destruction of the bony trabeculae, as well as abundant osteoid and new bone formation. The bone at the margins of the craniec tomy was normal in observation No. 1 but still tumoral in observation No. 2. In addition, in observation No. 2. 2 other features were notable: first, the small neuroblastic cells showed numerous mitoses: second, edematous and necrotic changes were present in the undifferentiated areas. Electron-Microscopic Findings
Numerous blocks from the second and third specimens were examined by transmission electron microscopy. This examination demonstrated two different tumor cell types: small cells representing the major cell population
Pierre-Kahn/Cinalli/Lellouch-Tubiana/ Villarejo/Sainte-Rosc/Pfistcr/Couly
Melanotic Neuroectodermal Tumors
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showed areas of black pigment. Their cut surface was greyish-yellow-black in color and of firm consistency. In the second case, the tumor was cystic and the cyst accounted for a significant fraction of the tumor volume.
and a few larger cells. The small cells were round, and intercellular junctions (desmosomes) were sometimes ob served between them. Their cytoplasm was rich in polyri bosomes and mitochondria. The large pigmented cells had irregular nuclei. Their cytoplasm was abundant and contained numerous mitochondria, a rough endoplasmic reticulum, and a well-developed Golgi apparatus. Melanosomes. in various stages of maturation, were observed: elongated premelanosomes, showing a characteristic la mellar structure, and mature clectrodense melanosomes (fig. 9). Immunohistochemical Findings Immunohistochemistry was performed in the second case. The results of this study are summarized in table 1.
Table 1. Immunohistochemical findings in case 2
Neuron-specific enolase SI 00 protein Vimentin Cytokeratin Glial fibrillary acidic protein1 Neurofilaments Carcinoembryonic antigen a-Fetoprotein Desmin Leucocyte-common antigen
Small cells
Large cells
+
++ +++ ++ + + — —
—
-
—
1 Astrocytes, glial fibrillary acidic protein positive, were present within the tumor.
Discussion
For Parizek et al. [20] who reviewed the literature up to 1986. 72.5% of MNTI were located at the mandible, the maxillary or the jaw, 19% at the skull, and 8% elsewhere in the body. Cases of interest for neurosurgeons are those which involve the brain, the dura, or the skull. The existence of MNTI of the brain is subject to dis cussion. Actually, most of the 20 cases reported by Shuangshoti [5, 21] and by Parizek et al. [20] have histo logical features akin to or the same as melanotic medullo blastomas or ependymomas [22-37], Only a few [38] could be true MNTI on the basis of their histological fea tures. MNTI of the brain, if they exist, have a constantly dismal prognosis due to recurrences or metastasis. For Cohen et al. [38], this could result from the predominance in the tumor of the neuroblast-like cell population. MNTI inserted on the dura and respecting the vault are rare. They are illustrated by our third case. Extending intracraniallv they are usually confused with other neo plasms, mainly meningioma and glioma. The skull is the most common location for MNTI. Including two of our observations, 28 cases (tables 2. 3) are now available for study [2, 4. 11, 13. 16. 17, 20, 3957], Probably due to the relative rarity of MNTI and therefore to physicians’ inexperience, their diagnosis is rarely made preoperatively despite a rather typical pre sentation. Their main symptom is a rapidly growing swelling which deforms the scalp. This swelling is gener ally located on or close to the midline (table 3) (18/28 cases), especially in the vicinity of the anterior fontanelle. Sometimes, however, it develops laterally (table 4) from the mastoid (2 cases), temporal (4 cases), or frontoorbital (3 cases) regions. The explosive development of the disDownloaded by: King's College London 137.73.144.138 - 11/27/2017 8:16:32 AM
MNTI are a rare but clearly delineated entity. Their gross appearance, as illustrated by our 3 cases, is always that of a solid, pigmented mass: a cyst may exist in addi tion but is a rare feature (observation No. 2). The prominent finding leading to diagnosis of these lesions is microscopic identification of two types of cells: small, undifferentiated and nonpigmented cells, and larg er, pigmented and epithelial-like cells. The ultrastructural (observations 2 and 3) and immunohistochemical (obser vation 2) studies that we performed correlate with the results obtained by others [7, 14-18]: the small neuroblast like cells show positivity with neuron-specific enolase but negativity for all other markers. Although such staining may be nonspecific, it is present in all tumors of neural crest origin and typically in neuroblastomas. The melanocytic large pigmented cells react against neuron-specific enolase, SI00 and Vimentin-like melanocytic tumors [17], They contain in their cytoplasm melanosomes at various stages of maturation, indicating their neural crest origin. The presence of melanin in a neoplasm immediately sug gests the diagnosis of melanoma. In our cases, however, the presence of two cell populations including undifferen tiated neuroblast-like elements excludes this diagnosis. Melanin pigment has been found in several primary cen tral nervous system tumors [19], in particular in medullo blastomas. ependymomas and pineoblastomas. The pig mented papillary variant of cerebellar medulloblastoma is often considered to be closely related to MNTI [20, 21], However, microscopically the picture is quite distinctive and melanotic medulloblastomas behave rather more like a medulloblastoma than MNTI.
Table 2. Intracerebral tumors published under the denomination of melanotic neuroectodermal tumors
Authors
Age
Sex
Site
Follow-up
Rubinstein and Northfield [30] Stowens [35]
8y 2iy NA NA NA 3y 30y ly 38y 4m 21 y 30y NA NA 1ly 6m I4y 69y NA 17w
NA NA NA NA NA M NA M M F M F NA NA NA M M M NA NA
PCF PCF PCF PCF PCF PCF PCF pineal PCF 3rd V PCF LT PCF T PCF B stem sellar PCF NA pineal
D NA NA NA NA D NA D D D A A NA NA NA D NA A NA A
Fowler and Simpson [25] Rubinstein [19] Best [10] Sung el al. [36] Stowens and Lin [ 1] Hahn et al. [26] McCloskcy et al. [28] Boesel et al. [23] Araoz and Moore [22] Ishida et al. [27] Shuangshoti [21] Tobo et al. [37] Shuangshoti [5] Russeger et al. [31] Cohen et al. [38]
2.5v
3w 5w 2m 18m 9m 18m
2m 9m 30m
w = Weeks; m = months: y = years: M = male; F = female; PCF = posterior cranial fossa; B stem = brain stem: L = left; T = temporal: 3rd V = third ventricle; A = alive: D = death: NA = not available.
Table 3. MNTI of neurocranium with midline localization
Authors
Age
Sex
Race
Site
Durai Adherence
Follow-up
Clarke and Parsons [4] Kuhn et al. [54] Davis [47] Reyes et al. [56] Neustein [16] Allen et al. [2] Grave and Mills [51] Gilmore and Mealey [50] Best [10] De Pascalis et al. [48] Adeloye et al. [39] Kasumova et al. [52] Bignold and Nicks [45] Lamping et al. [55] Stirling et al. [17] Atkinson et al. [43] Present series (1991)
9m 3m 4m 4m 6m 4m 4m 5m 5m 6m 5m 2y 7m 3m 6w 2m 2m iy
M F M F M M F M F F M F F M F F F M
W B B B B NA NA B NA W B W B W B NA FE B
AF AF AF AF AF AF PF AF AF AF AF AF AF AF AF AF AF AF
ED+ID NA ED+ID ED ED ED ED+ID ED+ID ED+ID ED+ID ED ED+ID NA ED NA ED+ID ED+ID+SD ED+ID+SD
14m A D postop D postop A NA A 7y D postop A 22m D postop A 4y D postop D postop D biopsy Rcc 3m, A 7m NA Rec 1m. A 1y A 8y Rec+ Met 5m
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Melanotic Neuroectodermal Tumors
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w = Weeks: m = months; y = years; M = male; F = female; W = White; B = Black; FE = Far East: AF = anterior fontanel = PF = posterior fontanel: ED = extradural: ID = Intradural; SD = Subdural: A = alive; D = death: Postop = postoperative; Rec = recurrence; Met = metastasc; NA = not available.
Table 4. MNTI of ncurocranium with lateral localization
Authors
Age
Sex
Race
Site
Durai adherence
Follow-up
Ashley [42] Koudstaal et al. [53] Anagnostopoulos and Everard [41] Alipccnko et al. [40] Doolinget al. [49] Walsh and Strand [13] Johnson et al. [11] Parizck et al. [20] Causeret ct al. [46] Salomao and Duarte [57] Present series (1991)
2m 2m 7m
M M M
NA B NA
RM RT LFT
ED ED ED
A A A
6m
15m 6m 4m 5m 33m 4m 3m 3y
F M M M M F F F
NA NA B W NA Magh W W
NA R FT RZ+RP RT RT RM LT LT
NA ED ED ED ED+ID+SD ED ED+ID+SD ID+SD
NA NA A A A A D A
6y 2y 6y 2y 9m 8y
16m
m = Months: y = years; M = male: F = female: W = White; B = Black; Magh = Maghrebian; R = right; L = left; F = frontal; T = temporal; P = parietal; M = mastoid; Z = zygomatic; ED = extradural; ID = intradural: SD = subdural: A = alive: D = dead: NA = not available.
dura where most patients are definitively cured once the tumor is totally resected. This is illustrated by our obser vations 1 and 3. However, local recurrences are possible [62], and cases with a malignant course have been re ported [59, 61, 63-69]. Local recurrences are explained either by subtotal removal of the lesion [57, 62], or by a multicentric origin of the tumor [ 13, 62, 70. 71 ]. A malig nant course was noted in the second of our 3 observations: the tumor not only recurred locally but also spread through a cerebral hemisphere. Of the 3 tumors of our series, this was the only one to present necrosis and numerous mitoses in its neuroblastic component. In addi tion. the margins of the craniectomy were infiltrated with tumor. In retrospect, these features alone should have been sufficient to indicate the aggressiveness of the tumor and therefore the necessity for complementary postopera tive treatment, not irradiation because of the very young age of the patient, but chemotherapy. It is of great interest that cyclophosphamide and carboplatin, when adminis tered at the time of recurrence and métastasés, led in 2 months to disappearance of one of the métastasés and to regression in size of the recurrence and of the second metastasis. Similar findings were observed bv Cohen et al. [38]. Surgical removal of MNTI of the skull and meninges may be difficult depending upon its localization. For lesions located laterally resection is usually uneventful, and in the literature the operative mortality in these cases is nil. On the contrary, operation may be difficult and dangerous for midline tumors. This is due to adherence of
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ease and the further radiological evidence of a bony tumor with inlratumoral spiculations explain that the first diag nosis is often alarming, eg. osteosarcoma. However, in most cases, this error could have been avoided if suffi cient diagnostic importance had been given to apparently minor clinical features: (l)age of onset; before 1 year in 86.2% of the cases (25/29 cases); (2) the absence of pain and inflammation at the level of the lesion; (3) the con stant normality and mobility of the scalp covering the swelling. To these features, one can add a less important criterion, which is the frequent occurrence of the disease in non-Caucasian patients: 10 Black. 1 Asiatic and 1 patient from North Africa, out of the 17 patients for whom this information is known. Two investigations can help to predict the nature and location of the tumor, and whether the lesion is situated intra- or extracranial. The first is magnetic resonance imaging [43] since melanin-containing tumors show, as in our case 2, areas of increased signal on T r weighted images and decreased signal on T^-wcighted images. The second investigation is the determination of HVA and VMA in the urine and in the cyst if any. and a-fetoprotein in the serum, since these levels may be high [3. 8. 43, 5861]. Even when this was not the case in the urine of the 2 patients of our series where such determinations were made, it is noteworthy that in the second of these patients, these levels were increased in the cyst fluid. Melanotic neuroectodermal tumors are generally con sidered to be benign with regard to their clinical course. This is true for most of the tumors of the skull and of the
the lesion to the dural sinus. In the literature, the conse quences of extensive intraoperative bleeding have been responsible for an operative mortality of 37.4% in young babies (table 1). For the same reasons. 1 of our patients had to be resuscitated during the operative procedure. Different theories have been put forth to explain the origin of these tumors, leading in the past to different denominations. Electron microscopy [7, 15, 53. 59] and histochemical studies [14. 17] have now established the neural crest as the most likely origin of these tumors. Three main observations argue in favor of this theory: first, the ultrastructural and histochemical similarities between the cells found in these tumors and both the melanocytes and neuroblasts which issue from the neural crest [72]: second, the high excretion level of HVA and VMA found in these tumors and in tumors known to have a neural crest origin such as pheochromocytomas. neuro blastomas or ganglioneuromas; third, the localization of these tumors in sites, or in the vicinity of structures, which are now known to derive from the neural crests.
This is the case for the skull on the midline [72, 73], the dura [72. 73] and the arachnoid villi [13]. The latter are present not only on the midline close to the sagittal sinus but also laterally, over the sphenoparietal venous sinus, the lateral or transverse sinus and the middle meningeal veins [13].
Conclusion
The preoperative diagnosis of MNTI remains difficult in spite of a frequently characteristic clinical presenta tion. Removal may be life threatening when they are located on the midline due to the risk of sudden blood loss during operation and its immediate consequences in young babies. If in most cases the clinical course is benign once totally removed, in a few it may be malig nant. Mitosis and necrosis may be findings of prognostic value that make systematic postoperative chemotherapy mandatory.
1 Stowens D. Tung-Hui Lin: Melanotic progonoma of the brain. Hum Pathol 1974;5:105— 113. 2 Allen MS, Harrison W. Jahrsdoerfer RA: ‘Reti nal anlage’ tumors, melanotic progonoma. me lanotic adamantinoma, pigmented epulis, me lanotic neuroectodermal tumor of infancy, be nign melanotic tumor of infancy. Am J Clin Pathol 1969:51:309-314. 3 Me Donald F: A case report of neuroectoder mal tumor of infancy. Br J Oral Maxillofac Surg 1985:23:227-229. 4 Clarke BE. Parsons H: An embryological tumor of retinal anlage involving the skull. Cancer 1951:4:78-85. 5 Shuangshoti S: Melanotic primitive neuroec todermal (neuroepithelial) tumor of medulla. J Surg Oncol 1986:33:37-42. 6 Pindborg JJ, Kramer IRH, Torloni H: Histo logical Typing of Odontogenic Tumors. Jaw Cysts and Allied Lesions. Geneva. World Health Organization. 1971. p 31. 7 Cutler LS. Chaudry AP. Topazian R: Mela notic neuroectodermal tumor of infancy: An ultrastructural study, literature review and reevaluation. Cancer 1981:48:257-270. 8 Borello ED. Gorlin RJ: Melanotic neuroecto dermal tumor of infancy - A neoplasm of neu ral crest origin. Cancer 1966; 19:196-206. 9 Carpenter B. Jimenez C. Robb I: Melanotic neuroectodermal tumor of infancy. Pediatr Pa thol 1985;3:227-244. 10 Best PV: Pigmented tumour arising in the skull of an infant. J Pathol 1972;107:69-72.
11 Johnson RE. Scheithauer BW, Dahlin DC: Me lanotic neuroectodermal tumor of infancy. Cancer 1983:52:661-666. 12 Lurie HI: Congenital melanocarcinoma, mela notic adamantinoma, retinal anlage tumor, progonoma. and pigmented epulis of infancy. Cancer 1960:14:1090-1108. 13 Walsh JW. Strand RD: Melanotic neuroecto dermal tumor of the neurocranium in infancy. Childs Brain 1982:9:329-346. 14 Melissari M. Tragni G. Gactti L. Gabriclli M. Bozzetti A. Raffaini M: Melanotic neuroecto dermal tumor of infancy (MNTI). Immuno histochemical and ultrastructural study of a case. J Craniomaxillofac Surg 1988:16:330— 336. 15 Misugi K, Okajima H. Newton WA. Kmetz DR. de Lorimier AA: Mediastinal origin of a melanotic progonoma or retinal anlage tumor. Ultrastructural evidence for neural crest origin. Cancer 1965:18:477-483. 16 Neustein HB: Fine structure of a melanotic progonoma or retinal anlage tumor of the ante rior fontanel. Exp Mol Pathol 1967:6:131— 142. 17 Stirling RW, Powell G: Fletcher CDM: Pig mented neuroectodermal tumor of infancy: An immunohistochemical study. Histopalhology 1988;12:425-435. 18 Taira Y. Nakyama 1. Takahara O. Moriuchi A. Yokoyama S, Maekawa N, Teruo I. Ynai M. Tsuji Y: Histological and fine structural studies on pigmented neuroectodermal tumor of infan cy. Acta Pathol Jpn 1978:28:83.
19 Rubinstein LJ: Tumor of the central nervous system: in ‘Atlas of Tumor Pathology', series 2, fascicle 6. Washington. Armed Forces Institute of Pathology, 1972, p 141. 20 Parizek J. Nemececk S. Cernoch Z, Heger L., Nozicka Z. Spacek J: Melanotic neuroectoder mal neurocranial tumor of infancy of extra-, intra- and subdural right temporal location: CT examination, surgical treatment, literature re view. Neuropediatrics 1986:17:1 15-123. 21 Shuangshoti S: Melanotic mucin-producing neuroepithelial neoplasm of mesencephalon with consideration of similar tumors in differ ent locations. J Neurol Neurosurg Psychiatry 1980;43:810-817. 22 Araoz C. Moor JJ: Melanotic neuroectodermal tumor of the middle fossa: Ullrastructural and biochemical study (abstract). J Neuropathol Exp Neurol 1979:38:303. 23 Bocsel S, Sultan JP. Sayers MP: Melanotic me dulloblastoma: Report of a case with ultrastructural findings. J Neuropathol Exp Neurol 1978:37:531-534. 24 Duinkerke SJ. Sloof JL. Gabreels FJM. Renier WO. Thijssen HOM. Biesta JH: Melanotic rhabdomyomedulloblastoma or teratoid tumor of the cerebellar vermis. Clin Neurol Neuro surg 1981:83:29. 25 Fowler M. Simpson DA: A malignant melanin forming tumor of the cerebellum. J Pathol Bacteriol 1962;84:307-311. 26 Hahn JF. Sperber F.E. Nctsky MG: Melanotic neuroectodermal tumors of the brain and skull. J Neuropathol Exp Neurol 1976;35:508-519.
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References
44 Best PV: A medulloblastoma-like tumor with melanin formation. J Pathol Bacteriol 1973: 110:101-111. 45 Bignold LP. Nicks R: Melanotic neuroectoder mal tumor of infancy arising in anterior fonta nelle. Pathology 1980:12:473-477. 46 Causeret M, Sainte-André JP. Cerez-Pham H. Rousselet MC, Guy G, Simard C: Progonome mélanotiquc intracrânien. Arch Anat Cytol Pa thol 1987;35:45-48. 47 Davis RL: Case number eleven of Slide Semi nar Session of the 38th Annual Meeting of the American Session of Neuropathologists. Atlan tic City. 1962. 48 De Pascalis C. Mastriacovo P. Mastrangelo R: A melanotic neuroectodermal tumor of infanev arising from the anterior fontanel. Tumori 1977;63:373-380. 49 Dooling EC. Chi JG. Gilles FH: Melanotic neu roectodermal tumor of infancy. Its histological similarities to fetal pineal gland. Cancer 1977; 39:1535-1541. 50 Gilmore RL. Mealey J: Melanotic neuroecto dermal tumor involving the cranium in infan cy. J Neurosurg 1972;36:507-511. 51 Grave GF. Mills AE: Retinal anlage tumors. J Pediatr Surg 1972:7:36-39. 52 Kasumova SJ. Komarov VI. Alipcenko LA: Slucaj melanoticeskoj progonomy svoda cere pa. Vopr Neurochir 1978:1:46-49. 53 Koudstaal J. Oldhoff J. Panders AK, Hardonk MJ: Melanotic neuroectodermal tumor or in fancy. Cancer 1968;22:151 -161. 54 Kuhn R. Cabanne F. Garneau R: Le rétinoblas tome pigmentaire hétérotopique. Rapport d'un cas et étude générale. Semin Hop Paris (Archs Anat Path) 1954:30:178. 55 Lamping KA, Albert DM. Lack E, Dickersin GR. Chapman PH. Walton DS: Melanotic neu roectodermal tumor of infancy (retinal anlage tumor). Ophtalmology 1985;92:143-149. 56 Reyes HA. Gonzales-Angulo A. NavarreteReyna A: 'Retinal anlage tumor of infancy’: Report of a case occurring in the anterior fonta nel. J Pediatr 1964.64:268-271. 57 Salomao JF, Duarte F: Progonoma melanotico craniano. Tumor neuro-ectodermico melano tico da infancia. Arq Bras Neurochir I989;8: 47-52. 58 BrekkeJB. Gorlin RJ: Melanotic neuroectoder mal tumor of infancy. J Oral Surg 1975:33: 858. 59 Dehner LP. Sibley RK. Sauk JJ. Vickers RA. Nesbit ME. Leonard AS. Waite DE, Neeley JE. Ophoven J: Malignant melanotic neuroecto dermal tumor of infancy. Cancer 1979:43: 1389-1410.
60 Dourov N. Mayer R. De Martelaere F. Godart S, Gepts W. Maurus R: Melanotic neuroecto dermal tumor of infancy with high scrum levels of alpha-fetoprotein. Oral Pathology 1987:16: 251-255. 61 Hamced K. Burslem MR: A melanotic ovarian neoplasm resembling the 'retinal anlage’ tu mor. Cancer 1970:25:564-567. 62 Nagase M. Ueda K. Fukushima M. Nakajima T: Recurrent melanotic neuroectodermal tu mour of infancy. J Maxillofac Surg 1983; 1 I: 131-136. 63 Block JC. Waite DE. Dehner LP. Leonard AS. Ogle RG. Gatto DG: Pigmented neuroectoder mal tumor of infancy: An example of rarely expressed malignant behavior. Oral Surg Oral Med Oral Pathol 1981.49:279-285. 64 King ME. Mouradian JA. Micha JP. Chaganti RSK, Allen SL: Immature teratoma of the ovary with predominant malignant retinal an lage component. Am J Surg Pathol 1985:9: 221-231. 65 Lindahl F: Malignant melanotic progonoma. Acta Pathol Microbiol Scand 1970:78:532— 536. 66 Palacios JJN: Malignant melanotic neuroec todermal tumor. Cancer 1980:46:529-536. 67 Schulz DM: A malignant, melanotic neoplasm of the uterus, resembling the 'retinal anlage’ tumors. Am J Clin Pathol 1957:28:524-532. 68 Shira RA: Pigmented neuroectodermal tumor of infancy: An example of rarely expressed ma lignant behavior. Oral Surg 1980:49:279-285. 69 Shorky A. Brincr J. Makek M: Malignant mela notic neuroectodermal tumor of infancy: A case report. Pediatr Pathol 1986:5:217-223. 70 Steinberg B. Shuler C, Wilson S: Melanotic neuroectodermal tumor of infancy: Evidence for multicentricity. Oral Surg Oral Med Oral Pathol 1988:66:666-669. 71 Young S. Gonzalez Crussi F: Melanocytic neu roectodermal tumor of the foot. Report of a case with multicentric origin. Am J Clin Pathol 1985:84:371-378. 72 Le Douarin NM: The neural crest. Cambridge. Cambridge University Press. 1982. p 259. 73 Couly G. Le Douarin NM: Mapping of the early neural primordium in quail-chick chi meras: 2) The prosencephalic neural plate and neural folds: Implications for the genesis of cephalic human congenital abnormalities. Dev Biol 1986:120:198-214.
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27 Ishida Y. Kawarai M. Suzuki K, Nagaya T: Medulloblastoma-like tumor of the cerebellum with melanin formation (melanotic medullo blastoma). No To Shinkei 1979;31:813-821. 28 McCloskey JJ. Parker JC. Brooks WH. Blacker HM: Melanin as a component of cerebral glio mas: The melanotic cerebral ependymoma. Cancer 1976;37:2373-2379. 29 Panyathanya R. Chantarakul N: (1982) Mela notic ependymoma with distal metastasis. J Med Assoc Thai 1982;65:454-458. 30 Rubinstein U . Northfield DWC: The medullo blastoma and the so-called 'arachnoidal cere bellar sarcoma". Brain 1964:87:379-412. 31 Russcgcr L, Weiscr G. Grunert V: Intracranial manifestations of so-called 'melanotic neuroec todermal tumor of infancy: A choristoma with neural crest potentials. Wien Klin Wochenschr 1987;99:647-652. 32 Russell DS. Rubinstein U : Pathology of the Tumours of the Nervous System, ed 4. London. Edward Arnold, p 250. 33 Russell DS. Rubinstein U: Pathology of the Tumours of the Nervous system, ed 4. London. Edward Arnold p 212. 34 Stowens D: A pigmented tumor of infancy: The melanotic progonoma. .1 Pathol Bacteriol 73: 1957;43-5I. 35 Stowens D: ‘Pediatric Pathology’, ed 2. Balti more. Williams & Wilkins. 1966, p 401. 36 Sung JH. Mastri AR. Segal EL: Melanotic me dulloblastoma of the cerebellum. J Neuropathol Exp Neurol 1973:32:437-443. 37 Tobo M. Sumiyoshi A, Yamakawa Y: Sellar teratoma with melanotic progonoma. Acta Neuropathol 1981:55:71-73. 38 Cohen BH. Handler MS. De Vivo DC, Garvin JH. Hays AP. Carmel P: Central nervous sys tem melanotic neuroectodermal tumor of in fancy: Value of chemotherapy in management. Neurology 38:163-164. 39 Adeloye A, Morgan SP. Agliadiuno P, Bohrer S: Melanotic ameloblastoma (retinal anlagc tu mour) of the skull in a Nigerian child. Surg Neurol 1977;7:42-44. 40 Alipcenko LA. Arbatova GV. Rostovceva TF: Melanoticeskaja progonoma cerepa. Vopr Onkol 1976:22:95-98. 41 Anagnostopoulos DI. Everard GJH; Melanotic progonoma of the skull. J Neurol Neurosurg Psychiatry 1972;35:88-91. 42 Ashley DJB: Melanotic 'adamantinoma' of the skull. J Pathol Bacteriol 1964:87:179-181. 43 Atkinson GO. Davis PC. Patrick LE. Winn KJ. Ball TL Wyly JB: Melanotic neuroectodermal tumor of infancy. MR findings and a review of the literature. Pediatr Radiol 1989:20:20-22.
A. Pierre-Kahna G. Cinallia A. Lellouch-Tubiana0 F. J. Villarejob C. Sainle-Rosea A. Pfisterc G. Coulyd
Melanotic Neuroectodermal Tumor of the Skull and Meninges in Infancy
a Neurosurgery, Hôpital des Enfants Malades, Paris. France; b Nacional Infantile Nino Jesus, Madrid. Spain; ° Histopathology Laboratory, and d Stomatology, Hôpital des Enfants Malades. Paris, France
Abstract
Three cases of melanotic neuroectodermal tumors of infancy are presented. Two were localized on the midline, involving the skull and extending subdurally. One was located on the inner aspect of the dura and developed intracranially. Two had a benign course following gross total removal. One had a malignant course, recurring locally and spreading within the brain. The diffi culties of removing these tumors when they are implanted on the midline are stressed. Histological features of prognostic value are pointed out. Further support for neural crest origin of these tumors is given.
Few tumors have been named so variously as the mela notic neuroectodermal tumor. The most common de nominations have been melanotic progonoma [1], mela notic adamantinoma [2], pigmented epulis [3], and retinal anlage tumor [4], Since 1986 the official denomination is melanotic neuroectodermal tumor of infancy (MNTI) be cause most of these lesions develop early in infancy [5, 6]. Localization of MNTI in the skull or the dura is rare, although second in frequency after the maxilla and man dible [7], Out of over 200 reported MNTI, only 26 involve the calvarium. Excellent reviews have been written about these tumors, from both clinical [7-13] and histopathological [7, 14-17] standpoints. Three reasons, however, lead us to publish 3 new cases of neurosurgical interest. First, the symptoms are frequently misleading and there fore the diagnosis and subsequent treatment can be inap propriate. This is probably due to the rarity of MNTI and hence the limited clinical experience. Second, both their
clinical presentation and prognosis may differ from their classical description. Third, these tumors, when located on the midline, may be difficult and dangerous to re move.
Clinical Presentation Observation No. I A 2-month-old Laotian female was hospitalized on December 7, 1983, for a small lump at the anterior fontanel. In a few days, the mass increased dramatically in size (fig. 1). When seen in the Hopital des Enfants Malades in Paris, the child presented with a huge, pain less. fixed mass covered with normal skin. Skull films revealed a tumor at the site of the bregma measuring 6 X 10 cm and involving the frontal and both parietal bones. The lesion was characterized by a zone of hyperostosis surrounded on both sides by a corona of bony spicules giving typical sunburst patterns. There was no evidence of lytic destruction. A noncontrasted computed tomography (CT) scan demonstrated a well-delimited, hyperdense. heterogeneous mass in-
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KeyWords Melanotic tumors Neurocranium Infants Neural crest
volving the bony calvarium at the bregma and extending intracranially down to the corpus callosum. Following intravenous contrast injection, there was bright enhancement of the lesion (fig. 2). On angiography, its feeding arteries were branches of the two external carotid arteries, mainly the temporal and the anterior meningeal. The tumor was biopsied. but it proved impossible to decide between neuroblastoma and MNTI. Urinary levels of homovanillic acid (F1VA) and of vanilmandelic acid (VMA) were normal. Chemother apy (cyclophosphamide, adriamvein) failed to reduce the size of the tumor preoperatively. On January 13. 1983, the tumor was excised in toto and ‘cn bloc' by circumferential craniectomy through apparently normal bone margins. The tumor had perforated the dura, being both extra- and subdural. Its surface was flecked by black pigment. It had a firm and gritty consistency. The end of the surgical procedure was complicated by sudden bleeding from the sagittal sinus. A brief car diac arrest ensued and the child required resuscitation. The dural and skull defects were repaired by means of a film of Dacron and acrylic cranioplasty, respectively. The definitive histopathological diagnosis of the tumor was typical MNTI. The margins of the cran iectomy were tumor free. No complementary postoperative treat ment was given. Further development of a fluid collection inside the operative cavity required the insertion of a subduroperitoneai shunt. Seven years postoperatively, the child was tumor free and ncurologicallv normal.
Fig. 2. Case 1: CT scan after injection. Frontal view. An enhanc ing tumor extends subcutaneously and intracranially from both side of a median and paramedian frontal hyperostosis. The subgaleal component of the lesion is small as compared with its intracranial component.
Observation No. 2
A painless but rapidly growing left frontal swelling was first noted in a 12-month-old Black male. One month later, the infant was trans ferred to our unit at the Hopital des Enfants Malades in Paris. In the meantime, he had stopped walking and had become irritable. Upon admission, the bump was considerably larger than reported a few weeks earlier. The mass was fixed to the ncurocranium but not to the overlying scalp. In addition, the patient had brisk reflexes at the 4 limbs and a macrocranium at + 5 SD. The ocular fundi, however, were normal. Xerographies of the skull show'cd the inner and outer tables of the left frontal bone to be the seat of both dense sclerosis and hyperostosis; spicules irradiating in all directions from this hyperos tosis produced a sunburst appearance. CT scan confirmed these aspects and revealed, in addition, the presence of a huge contralateral enhancing intracranial cystic mass, shifting the midline and the ven tricles from right to left. On magnetic resonance without injection the major part of the mass was slightly hypointense as compared to the brain on both the Ti and Ti relaxation times. However, a small com ponent of the lesion was hyperintense on T|- and hypointense on Ti-weightcd images (fig. 3). After injection (fig. 4). there was bright enhancement of the whole solid mass. Selective angiographies showed a slight tumoral blush from anterior branches of both the external and internal right carotid arteries. Given the angiographic features, a biopsy was surprisingly complicated by hemorrhage, necessitating a 400-ml transfusion. Histological diagnosis of the sam ples was in favor of MNTI. To reduce the volume of the lesion before removing the tumor.a Rickham reservoir was inserted inside the cyst (03/01/90). The liquid, withdrawn daily, contained a high level of
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Fig. 1. Case 1: Xerographies demonstrating the considerable increase in size of the tumor of the skull at 2-month interval. The lesion, located on the midline, involves each edge of the coronal sutures and develops both subcutaneously and extradurally. The presence of hyperostosis is responsible fora sunburst appearcnce.
Fig. 3. Case 2: Magnetic resonance imaging. Frontal views. Without injection, the tumor is isointense to the surrounding brain tissue on both the Tj-(a) and Ti-(b) weighted images, except for a small part of it (arrow) which is hyperintense in Ti and hypointense in T \ This behavior is characteristic of melanin-containing tumors.
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Fourteen months after the first operation, the child was operated on again for local recurrence. The metastasis were completely removed, a ventriculoperitoneal shunt was inserted and a course of chemotherapy was reinitiated postoperatively. Three months post operatively, CT scan showed numerous enhancing nodules wide spread on the inner aspect of the dura and filling the lumen of the sagittal sinus above the level of the torcular. These nodules were interpreted as resulting from tumoral seeding. Observation No. 3
A 3-year-old White female was hospitalized on October 3, 1983, in the neurosurgical department of the Hospital Nacional Infantil Nino Jesus in Madrid after a left focal seizure. Clinical examination was normal, particularly the shape of her skull. On standard X-rays, there was a round-shaped right pterional calcified mass (fig. 5). CT scan revealed an intracranial, heterogeneous and enhancing tumor, attached to a thickened and dense right pterion. The brain surround ing the tumor was hypodensc and edematous (fig. 6). As demon strated by right carotid angiography, the blood to the tumor was sup plied exclusively by anterior temporal branches of the external carot id. The child was operated on November 8, 1983. Intraoperatively, the vault was normal. The pterion was the seat of hyperostosis. The tumor, exclusively subdural, was firmly attached to the inner aspect of the dura covering the pterion, clearly delimited from the overlying brain. The tumor was removed in toto with its dural attachment. On the surface, it was diffusely darkly pigmented. No complementary postoperative treatment was given. Seven years later, the child was neurologically intact and free of disease.
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HVA (3.57 nmol/1) and VMA (136 nmol/l). However, 24-hour urine determination of these metabolites was normal. After repeated punc tures of the cyst, the child recovered a normal neurological condition and was then operated on (03/19/90). Craniectomy, passing far from the tumor, was performed. It was unclear, however, whether the bone was normal at its margin. The tumor itself had perforated the dura and obliterated the superior sagittal sinus, making possible the section and the removal of this part of the sinus. The subdural com ponent of the lesion, including its cystic portion, was easily divided from the adjacent brain and removed apparently in toto. The solid part of the tumor was diffusely black. The dural defect was closed with a film of Dacron. The defect at the skull was repaired I month later using an irradiated bone graft. Meanw hile, external hydroceph alus developed in the operative field, necessitating insertion of a subduroperitoneal shunt. Recovery was uneventful, and the infant was discharged within 5 weeks, neurologically intact, and. as seen on the postoperative CT scan, free of tumor. He was. however, rehospital ized on August 3. 1990. for the onset of left hemiparesis. On a new CT scan there was not only a right frontal recurrence, but also two intracranial mctastascs on the left side. Chemotherapy was initiated using cyclophosphamide (100 mg/nWday for 3 days) and carboplatin (100 mg/nWday for 3 days), and then cyclophosphamide ( 150 mg/nWday for 3 days) and etoposide (1 g/nWday for 3 days). In 2 months the left paramedian metastasis had cleared up, while the local recurrence and the occipital metastasis had reduced signifi cantly in size. Six months postoperatively, the images were stable and the child was in excellent general condition w'ith slight left hemi paresis.
Fig. 4. Case 2: Preoperative magnetic resonance imaging. Para median sagittal view. Demonstration after contrast injection of a huge enhancing intracranial mass associated with a deep intracere bral cyst and a frontal hyperostosis (arrows).
Fig. 5. Plain radiogram of the skull. Sagittal view. Presence of a round-shaped calcified lesion surrounding a hyperostotic pterion.
Fig. 6. Case 3: CT scan after injection. Axial views. Presence of a calcified heteroge neous, enhancing intracranial tumor at tached to a thickened hyperdense pterion. Note that the external aspect of the calvar ium at this level is normal.
Gross Features
In observations 1 and 2. the gross features were simi lar: the growths involved the vault and had both a subdu ral and extradural component. The 3rd observation dif
fered from the first two in that the vault was not tumoral, the tumor being only subdural and firmly attached to the inner aspect of the dura. In all 3 cases, however, the bone close to the lesion was the seat of sclerosis and hyperosto sis. In all cases, the tumors were large, measuring 6-9 cm in diameter. Their outer surface was multinodular and
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Pathology
Fig. 7. Microphotograph showing two cell types: small rounded undifferentiated cells (thin arrows) with scant cytoplasm and large brown cells (thick arrows). HE. X 324. Fig. 8. Microphotograph at higher magnification showing the two cell types and the presence of melanic pigment in the large-cell cyto plasm. X 1,200. Fig. 9. Electron micrograph of large pigmented cells. The cyto plasm contains electron-dense granules in various stages of matura tion (*). Uranyl acetate. Lead citrate X 4.000.
Miicroscopic Findings
The tumors were virtually similar in the routine prepa rations. The most striking feature was the presence of two distinct cell populations in the tumor (fig. 7). The first was composed of small rounded undifferentiated cells with hyperchromatic nuclei and scant cytoplasm. They were of ncuroblastic type, and the cells were arranged in the form of irregular nests and cords. Neither neuronal differentia tion nor rosette formation was seen. The second cell pop ulation consisted of large cells with vesicular nuclei and eosinophilic cytoplasm, frequently containing fine granu lar melanic pigment (fig. 8). This pigment did not stain with the Prussian blue stain for iron but was strongly posi tive with the Fontana method for melanin. These large
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pigmented cells affected pseudoalveolar patterns dis persed within the stroma. This stroma was composed of hypocellular dense collagenous connective tissue. In the first two observations, the tumor invaded the surrounding bone. There was extensive destruction of the bony trabeculae, as well as abundant osteoid and new bone formation. The bone at the margins of the craniec tomy was normal in observation No. 1 but still tumoral in observation No. 2. In addition, in observation No. 2. 2 other features were notable: first, the small neuroblastic cells showed numerous mitoses: second, edematous and necrotic changes were present in the undifferentiated areas. Electron-Microscopic Findings
Numerous blocks from the second and third specimens were examined by transmission electron microscopy. This examination demonstrated two different tumor cell types: small cells representing the major cell population
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showed areas of black pigment. Their cut surface was greyish-yellow-black in color and of firm consistency. In the second case, the tumor was cystic and the cyst accounted for a significant fraction of the tumor volume.
and a few larger cells. The small cells were round, and intercellular junctions (desmosomes) were sometimes ob served between them. Their cytoplasm was rich in polyri bosomes and mitochondria. The large pigmented cells had irregular nuclei. Their cytoplasm was abundant and contained numerous mitochondria, a rough endoplasmic reticulum, and a well-developed Golgi apparatus. Melanosomes. in various stages of maturation, were observed: elongated premelanosomes, showing a characteristic la mellar structure, and mature clectrodense melanosomes (fig. 9). Immunohistochemical Findings Immunohistochemistry was performed in the second case. The results of this study are summarized in table 1.
Table 1. Immunohistochemical findings in case 2
Neuron-specific enolase SI 00 protein Vimentin Cytokeratin Glial fibrillary acidic protein1 Neurofilaments Carcinoembryonic antigen a-Fetoprotein Desmin Leucocyte-common antigen
Small cells
Large cells
+
++ +++ ++ + + — —
—
-
—
1 Astrocytes, glial fibrillary acidic protein positive, were present within the tumor.
Discussion
For Parizek et al. [20] who reviewed the literature up to 1986. 72.5% of MNTI were located at the mandible, the maxillary or the jaw, 19% at the skull, and 8% elsewhere in the body. Cases of interest for neurosurgeons are those which involve the brain, the dura, or the skull. The existence of MNTI of the brain is subject to dis cussion. Actually, most of the 20 cases reported by Shuangshoti [5, 21] and by Parizek et al. [20] have histo logical features akin to or the same as melanotic medullo blastomas or ependymomas [22-37], Only a few [38] could be true MNTI on the basis of their histological fea tures. MNTI of the brain, if they exist, have a constantly dismal prognosis due to recurrences or metastasis. For Cohen et al. [38], this could result from the predominance in the tumor of the neuroblast-like cell population. MNTI inserted on the dura and respecting the vault are rare. They are illustrated by our third case. Extending intracraniallv they are usually confused with other neo plasms, mainly meningioma and glioma. The skull is the most common location for MNTI. Including two of our observations, 28 cases (tables 2. 3) are now available for study [2, 4. 11, 13. 16. 17, 20, 3957], Probably due to the relative rarity of MNTI and therefore to physicians’ inexperience, their diagnosis is rarely made preoperatively despite a rather typical pre sentation. Their main symptom is a rapidly growing swelling which deforms the scalp. This swelling is gener ally located on or close to the midline (table 3) (18/28 cases), especially in the vicinity of the anterior fontanelle. Sometimes, however, it develops laterally (table 4) from the mastoid (2 cases), temporal (4 cases), or frontoorbital (3 cases) regions. The explosive development of the disDownloaded by: King's College London 137.73.144.138 - 11/27/2017 8:16:32 AM
MNTI are a rare but clearly delineated entity. Their gross appearance, as illustrated by our 3 cases, is always that of a solid, pigmented mass: a cyst may exist in addi tion but is a rare feature (observation No. 2). The prominent finding leading to diagnosis of these lesions is microscopic identification of two types of cells: small, undifferentiated and nonpigmented cells, and larg er, pigmented and epithelial-like cells. The ultrastructural (observations 2 and 3) and immunohistochemical (obser vation 2) studies that we performed correlate with the results obtained by others [7, 14-18]: the small neuroblast like cells show positivity with neuron-specific enolase but negativity for all other markers. Although such staining may be nonspecific, it is present in all tumors of neural crest origin and typically in neuroblastomas. The melanocytic large pigmented cells react against neuron-specific enolase, SI00 and Vimentin-like melanocytic tumors [17], They contain in their cytoplasm melanosomes at various stages of maturation, indicating their neural crest origin. The presence of melanin in a neoplasm immediately sug gests the diagnosis of melanoma. In our cases, however, the presence of two cell populations including undifferen tiated neuroblast-like elements excludes this diagnosis. Melanin pigment has been found in several primary cen tral nervous system tumors [19], in particular in medullo blastomas. ependymomas and pineoblastomas. The pig mented papillary variant of cerebellar medulloblastoma is often considered to be closely related to MNTI [20, 21], However, microscopically the picture is quite distinctive and melanotic medulloblastomas behave rather more like a medulloblastoma than MNTI.
Table 2. Intracerebral tumors published under the denomination of melanotic neuroectodermal tumors
Authors
Age
Sex
Site
Follow-up
Rubinstein and Northfield [30] Stowens [35]
8y 2iy NA NA NA 3y 30y ly 38y 4m 21 y 30y NA NA 1ly 6m I4y 69y NA 17w
NA NA NA NA NA M NA M M F M F NA NA NA M M M NA NA
PCF PCF PCF PCF PCF PCF PCF pineal PCF 3rd V PCF LT PCF T PCF B stem sellar PCF NA pineal
D NA NA NA NA D NA D D D A A NA NA NA D NA A NA A
Fowler and Simpson [25] Rubinstein [19] Best [10] Sung el al. [36] Stowens and Lin [ 1] Hahn et al. [26] McCloskcy et al. [28] Boesel et al. [23] Araoz and Moore [22] Ishida et al. [27] Shuangshoti [21] Tobo et al. [37] Shuangshoti [5] Russeger et al. [31] Cohen et al. [38]
2.5v
3w 5w 2m 18m 9m 18m
2m 9m 30m
w = Weeks; m = months: y = years: M = male; F = female; PCF = posterior cranial fossa; B stem = brain stem: L = left; T = temporal: 3rd V = third ventricle; A = alive: D = death: NA = not available.
Table 3. MNTI of neurocranium with midline localization
Authors
Age
Sex
Race
Site
Durai Adherence
Follow-up
Clarke and Parsons [4] Kuhn et al. [54] Davis [47] Reyes et al. [56] Neustein [16] Allen et al. [2] Grave and Mills [51] Gilmore and Mealey [50] Best [10] De Pascalis et al. [48] Adeloye et al. [39] Kasumova et al. [52] Bignold and Nicks [45] Lamping et al. [55] Stirling et al. [17] Atkinson et al. [43] Present series (1991)
9m 3m 4m 4m 6m 4m 4m 5m 5m 6m 5m 2y 7m 3m 6w 2m 2m iy
M F M F M M F M F F M F F M F F F M
W B B B B NA NA B NA W B W B W B NA FE B
AF AF AF AF AF AF PF AF AF AF AF AF AF AF AF AF AF AF
ED+ID NA ED+ID ED ED ED ED+ID ED+ID ED+ID ED+ID ED ED+ID NA ED NA ED+ID ED+ID+SD ED+ID+SD
14m A D postop D postop A NA A 7y D postop A 22m D postop A 4y D postop D postop D biopsy Rcc 3m, A 7m NA Rec 1m. A 1y A 8y Rec+ Met 5m
12
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Melanotic Neuroectodermal Tumors
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w = Weeks: m = months; y = years; M = male; F = female; W = White; B = Black; FE = Far East: AF = anterior fontanel = PF = posterior fontanel: ED = extradural: ID = Intradural; SD = Subdural: A = alive; D = death: Postop = postoperative; Rec = recurrence; Met = metastasc; NA = not available.
Table 4. MNTI of ncurocranium with lateral localization
Authors
Age
Sex
Race
Site
Durai adherence
Follow-up
Ashley [42] Koudstaal et al. [53] Anagnostopoulos and Everard [41] Alipccnko et al. [40] Doolinget al. [49] Walsh and Strand [13] Johnson et al. [11] Parizck et al. [20] Causeret ct al. [46] Salomao and Duarte [57] Present series (1991)
2m 2m 7m
M M M
NA B NA
RM RT LFT
ED ED ED
A A A
6m
15m 6m 4m 5m 33m 4m 3m 3y
F M M M M F F F
NA NA B W NA Magh W W
NA R FT RZ+RP RT RT RM LT LT
NA ED ED ED ED+ID+SD ED ED+ID+SD ID+SD
NA NA A A A A D A
6y 2y 6y 2y 9m 8y
16m
m = Months: y = years; M = male: F = female: W = White; B = Black; Magh = Maghrebian; R = right; L = left; F = frontal; T = temporal; P = parietal; M = mastoid; Z = zygomatic; ED = extradural; ID = intradural: SD = subdural: A = alive: D = dead: NA = not available.
dura where most patients are definitively cured once the tumor is totally resected. This is illustrated by our obser vations 1 and 3. However, local recurrences are possible [62], and cases with a malignant course have been re ported [59, 61, 63-69]. Local recurrences are explained either by subtotal removal of the lesion [57, 62], or by a multicentric origin of the tumor [ 13, 62, 70. 71 ]. A malig nant course was noted in the second of our 3 observations: the tumor not only recurred locally but also spread through a cerebral hemisphere. Of the 3 tumors of our series, this was the only one to present necrosis and numerous mitoses in its neuroblastic component. In addi tion. the margins of the craniectomy were infiltrated with tumor. In retrospect, these features alone should have been sufficient to indicate the aggressiveness of the tumor and therefore the necessity for complementary postopera tive treatment, not irradiation because of the very young age of the patient, but chemotherapy. It is of great interest that cyclophosphamide and carboplatin, when adminis tered at the time of recurrence and métastasés, led in 2 months to disappearance of one of the métastasés and to regression in size of the recurrence and of the second metastasis. Similar findings were observed bv Cohen et al. [38]. Surgical removal of MNTI of the skull and meninges may be difficult depending upon its localization. For lesions located laterally resection is usually uneventful, and in the literature the operative mortality in these cases is nil. On the contrary, operation may be difficult and dangerous for midline tumors. This is due to adherence of
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ease and the further radiological evidence of a bony tumor with inlratumoral spiculations explain that the first diag nosis is often alarming, eg. osteosarcoma. However, in most cases, this error could have been avoided if suffi cient diagnostic importance had been given to apparently minor clinical features: (l)age of onset; before 1 year in 86.2% of the cases (25/29 cases); (2) the absence of pain and inflammation at the level of the lesion; (3) the con stant normality and mobility of the scalp covering the swelling. To these features, one can add a less important criterion, which is the frequent occurrence of the disease in non-Caucasian patients: 10 Black. 1 Asiatic and 1 patient from North Africa, out of the 17 patients for whom this information is known. Two investigations can help to predict the nature and location of the tumor, and whether the lesion is situated intra- or extracranial. The first is magnetic resonance imaging [43] since melanin-containing tumors show, as in our case 2, areas of increased signal on T r weighted images and decreased signal on T^-wcighted images. The second investigation is the determination of HVA and VMA in the urine and in the cyst if any. and a-fetoprotein in the serum, since these levels may be high [3. 8. 43, 5861]. Even when this was not the case in the urine of the 2 patients of our series where such determinations were made, it is noteworthy that in the second of these patients, these levels were increased in the cyst fluid. Melanotic neuroectodermal tumors are generally con sidered to be benign with regard to their clinical course. This is true for most of the tumors of the skull and of the
the lesion to the dural sinus. In the literature, the conse quences of extensive intraoperative bleeding have been responsible for an operative mortality of 37.4% in young babies (table 1). For the same reasons. 1 of our patients had to be resuscitated during the operative procedure. Different theories have been put forth to explain the origin of these tumors, leading in the past to different denominations. Electron microscopy [7, 15, 53. 59] and histochemical studies [14. 17] have now established the neural crest as the most likely origin of these tumors. Three main observations argue in favor of this theory: first, the ultrastructural and histochemical similarities between the cells found in these tumors and both the melanocytes and neuroblasts which issue from the neural crest [72]: second, the high excretion level of HVA and VMA found in these tumors and in tumors known to have a neural crest origin such as pheochromocytomas. neuro blastomas or ganglioneuromas; third, the localization of these tumors in sites, or in the vicinity of structures, which are now known to derive from the neural crests.
This is the case for the skull on the midline [72, 73], the dura [72. 73] and the arachnoid villi [13]. The latter are present not only on the midline close to the sagittal sinus but also laterally, over the sphenoparietal venous sinus, the lateral or transverse sinus and the middle meningeal veins [13].
Conclusion
The preoperative diagnosis of MNTI remains difficult in spite of a frequently characteristic clinical presenta tion. Removal may be life threatening when they are located on the midline due to the risk of sudden blood loss during operation and its immediate consequences in young babies. If in most cases the clinical course is benign once totally removed, in a few it may be malig nant. Mitosis and necrosis may be findings of prognostic value that make systematic postoperative chemotherapy mandatory.
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11 Johnson RE. Scheithauer BW, Dahlin DC: Me lanotic neuroectodermal tumor of infancy. Cancer 1983:52:661-666. 12 Lurie HI: Congenital melanocarcinoma, mela notic adamantinoma, retinal anlage tumor, progonoma. and pigmented epulis of infancy. Cancer 1960:14:1090-1108. 13 Walsh JW. Strand RD: Melanotic neuroecto dermal tumor of the neurocranium in infancy. Childs Brain 1982:9:329-346. 14 Melissari M. Tragni G. Gactti L. Gabriclli M. Bozzetti A. Raffaini M: Melanotic neuroecto dermal tumor of infancy (MNTI). Immuno histochemical and ultrastructural study of a case. J Craniomaxillofac Surg 1988:16:330— 336. 15 Misugi K, Okajima H. Newton WA. Kmetz DR. de Lorimier AA: Mediastinal origin of a melanotic progonoma or retinal anlage tumor. Ultrastructural evidence for neural crest origin. Cancer 1965:18:477-483. 16 Neustein HB: Fine structure of a melanotic progonoma or retinal anlage tumor of the ante rior fontanel. Exp Mol Pathol 1967:6:131— 142. 17 Stirling RW, Powell G: Fletcher CDM: Pig mented neuroectodermal tumor of infancy: An immunohistochemical study. Histopalhology 1988;12:425-435. 18 Taira Y. Nakyama 1. Takahara O. Moriuchi A. Yokoyama S, Maekawa N, Teruo I. Ynai M. Tsuji Y: Histological and fine structural studies on pigmented neuroectodermal tumor of infan cy. Acta Pathol Jpn 1978:28:83.
19 Rubinstein LJ: Tumor of the central nervous system: in ‘Atlas of Tumor Pathology', series 2, fascicle 6. Washington. Armed Forces Institute of Pathology, 1972, p 141. 20 Parizek J. Nemececk S. Cernoch Z, Heger L., Nozicka Z. Spacek J: Melanotic neuroectoder mal neurocranial tumor of infancy of extra-, intra- and subdural right temporal location: CT examination, surgical treatment, literature re view. Neuropediatrics 1986:17:1 15-123. 21 Shuangshoti S: Melanotic mucin-producing neuroepithelial neoplasm of mesencephalon with consideration of similar tumors in differ ent locations. J Neurol Neurosurg Psychiatry 1980;43:810-817. 22 Araoz C. Moor JJ: Melanotic neuroectodermal tumor of the middle fossa: Ullrastructural and biochemical study (abstract). J Neuropathol Exp Neurol 1979:38:303. 23 Bocsel S, Sultan JP. Sayers MP: Melanotic me dulloblastoma: Report of a case with ultrastructural findings. J Neuropathol Exp Neurol 1978:37:531-534. 24 Duinkerke SJ. Sloof JL. Gabreels FJM. Renier WO. Thijssen HOM. Biesta JH: Melanotic rhabdomyomedulloblastoma or teratoid tumor of the cerebellar vermis. Clin Neurol Neuro surg 1981:83:29. 25 Fowler M. Simpson DA: A malignant melanin forming tumor of the cerebellum. J Pathol Bacteriol 1962;84:307-311. 26 Hahn JF. Sperber F.E. Nctsky MG: Melanotic neuroectodermal tumors of the brain and skull. J Neuropathol Exp Neurol 1976;35:508-519.
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