Introduction

Neurocutaneous melanosis (NCM) is a rare phacomatosis; about 100 cases have been reported in the literature. The diagnosis rests on finding giant congenital melanotic nevi along with abnormal melanin deposits in the brain or leptomeninges documented by magnetic resonance imaging (MRI) [1, 4, 6, 12, 15, 20, 22, 30, 32] or autopsy studies. The association of this disease with the Dandy-Walker complex (DWC) is even more infrequent with only 11 previous cases found in the literature [7, 11, 12, 18, 28, 34]. An embryological explanation for the origin of this association is lacking. Seizures and hydrocephalus have been reported as early manifestations of NCM with psychiatric symptoms described in the adult-onset form [29]. The clinical course is marked with death presenting in early childhood due to primary central nervous system melanomas. DWC is a hindbrain malformation attributed to an induction failure of the cerebellar plates resulting in partial or total agenesis of the vermis along with failure of perforation of the fourth ventricle. Recently, Di Rocco et al. cited a 10% incidence of NCM associated with cystic malformations of the posterior fossa [12].

Case report

The patient was a 1-year-old female, product of an eventful pregnancy and labor. Upon birth, multiple melanocytic nevi were noted, with lesions greater than 6 cm in width in the genitals, the right calf and the dorsal midline as well as 34 different-sized nevi, scattered on the torso, limbs, and scalp (Figs. 1, 2). She had normal neurodevelopmental milestones until 4 months of age, when she presented with nonfebrile tonic–clonic seizures that required anticonvulsant therapy with phenobarbital. Because of increased head circumference the patient was referred to our institution for evaluation. A computed tomography (CT) scan revealed ventricular enlargement and a posterior fossa cyst compatible with a DWC as described by Barkovich et al. [3]. Due to the presence of the multiple nevi and the CT findings, she was further evaluated with magnetic resonance gadolinium-enhanced imaging. The images showed shortening of T1-weighted signals in the amygdala, anterosuperior cerebellar surface as well as the rostral brain stem (Fig. 3). There were also imaging findings consistent with the DWC. Ventricular enlargement was also noted (Fig. 4). The patient was taken to the operating room (OR) and a left suboccipital burr hole was fashioned so that a neuroendoscope could be inserted into the cyst cavity with the purpose of fenestrating the cyst’s wall into the basal cisterns in an attempt to avoid shunting. The cyst pressure was measured at 5 cm/H2O. Direct optical exploration of the cyst walls did not reveal particular areas of melanin deposits, and a fenestration of the wall was made into the cisterna magna. The patient had an uneventful recovery and was discharged home, but she returned 5 days later with a CSF leak that was complicated by bacterial meningitis. Cultures were consistent with Staphylococcus aureus. CSF cytology did not reveal melanocytic cells. An external ventricular drain was placed and she received a full course of antimicrobial therapy. When cultures and CSF parameters improved, she was taken again to the OR for ventriculoperitoneal (VP) shunting. At the 1-year follow-up, she had occasional seizures and there had been a slight delay in the completion of neurodevelopmental milestones with no evidence of malignant melanocytic activity in the skin or the nervous system.

Fig. 1
figure 1

Large congenital melanocytic nevi (LCMN) in the external genitals

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Fig. 2a, b
figure 2

LCMN in the right calf and in the dorsal midline with multiple satellite nevi

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Fig. 3
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T1-weighted image showing hyperintensity of both amygdala, rostral brain stem, and cerebellar folia

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Fig. 4
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T1-weighted images with high-lying torcular, partial vermian agenesis, and enlarged fourth ventricle, findings consistent with the Dandy-Walker complex; note the ventricular enlargement

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Discussion

The initial pathological description of NCM was published by von Rokitanski in 1861 [40]. Later, in 1948 Van Bogaert recognized the clinical relationship of congenital melanocytic nevi with leptomeningeal melanosis or primary melanomas of the CNS [38], and the first clinical series were published by Touraine in 1949 [37].

NCM is a rare disease with unknown familial occurrence, which occurs equally in both sexes. The prevalence of malignant transformation into malignant melanoma is about 40–60% of cases with death presenting shortly after evidence of CNS compromise [20].

Benda has attributed the DWC [5] to a failure of normal regressive changes in the posterior medullary velum with partial or total vermian agenesis and cystic dilatation of the fourth ventricle, with separation of the cerebellar hemispheres. It is important to state that this phenomenon takes place at an embryological stage prior to the expected time line in which the fourth ventricle foramina become patent (28 vs 50 gestational days) [23], casting doubt on the foraminal atresia theory upheld for decades [36]. There are other common structural defects associated with DWC such as corpus callosum agenesis and neuronal migration disorders which cannot be explained by the latter theory [27]. The association of both entities can be traced back to 1931 and there have been only 11 subsequent reports [7, 11, 12, 13, 18, 28, 34].

Cramer was the first to propose that the melanocytes have a neural crest origin and that these cells travel in a centrifugal pattern along autonomic and sensory nerves, vascular and adnexal structures [10]. It has been postulated that spontaneous somatic mutations of the c-Met proto-oncogene and overexpression of the hepatocyte growth factor will promote the abnormal expression of melanin genes with the occurrence of large congenital melanocytic nevi and, probably, CNS melanotic tumor formation [21, 22]. Whether this mechanism may influence the hindbrain formation with the resulting DWC is unlikely due to the rare concurrence of these two congenital events.

The classic diagnostic criteria of NCM were defined by Fox et al. in 1972 [15] and later reviewed and summarized by Kadonaga and Frieden [20] (see Table 1).

Table 1 Kadonaga and Frieden criteria for the diagnosis of neurocutaneous melanosis [20]
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The clinical pattern of presentation follows the pathological level of compromise: (1) focal disease with seizures, aphasia, psychiatric manifestations, or failure to achieve neurodevelopmental milestones as an expression of the cortico-subcortical irritative process, paraparesis, paraplegia, and sphincter dysfunction from medullary compression etc., (2) evidence of increased intracranial pressure related to CSF pathway blockage (headache, increased head circumference, fontanel bulging, papilledema, oculomotor paresis, and Parinaud’s syndrome), and (3) a combination of these features {1, 9, 11, 12, 18, 20, 22, 25, 28, 30, 31, 35].

There are normal numbers of melanocytes within the pia-arachnoid particularly in the basal surface of the cerebellum, frontal, temporal, and occipital lobes as well as on the brain stem, reticular formation and substantia nigra [17]. Spinal myelopathy has been associated with invasion or leptomeningeal infiltration with formation of pseudoarachnoid cysts and secondary syringomyelia [30, 31].

The macroscopic histological features of NCM have been described as thickening of the leptomeninges by infiltrative tumor cells with predilection for the basal surface of the brain as well as the rostral portion of the brain stem. Lesions over the convexity, although infrequent, can associate with invasion of the brain parenchyma [18, 35].

The classic microscopic appearance is invasion of the Virchow-Robin spaces, with three types of lesions: (1) S-type or spindle patterns with interlaced bundles of cells, (2) R-type or mosaic pattern with polyhedral cells with large cytoplasm and clear nucleus, and (3) W-type with numerous cells presenting vesicular nuclei and scant cytoplasm [15]. To increase the specificity of the histological diagnosis, tissue samples should be studied with conventional light microscopy, electron microscopy, and immunohistochemical staining for S-100 and HMB-45 [15, 20, 32, 42].

Evidence of melanocytic activity is determined by the presence of melanocytes in a CSF sample or in a leptomeningeal biopsy. Histological features of malignancy are: mitotic activity, annulate lamellae, invasion of the basal lamina of blood vessels at the Virchow-Robin space, and necrosis [32, 42]. The reported phakomatoses associated with NCM are neurofibromatosis and the Sturge–Weber–Dimitri syndrome [7].

Barkovich et al. [3, 4, 16] described the principal MRI characteristics of NCM, which are consistent with a shortening of T1-weighted studies resulting in hyperintense signal intensity. Also, some cases have demonstrated images with shortening in T1- and T2-weighted post-gadolinium sequences. Edema or mass effect in inactive deposits of melanin are lacking; however, a pattern of enhancement with the administration of gadolinium in previously nonenhancing lesions can suggest malignant disease [33]. Such MR imaging features have been attributed to the magnetic proprieties of melanin, which have been related to the high index of free radicals contained in the indol-semiquinones and semiquinonines. However, there is a previous report in which CNS lesions of metastatic melanoma failed to show these features [42] while the report of a primary amelanotic melanoma did [39]. MRI differential diagnosis of T1 shortening includes the presence of calcium, fat, or subacute hemorrhage, which can be excluded by observing the chemical shift artifact in the former and the high T2 signal intensity in the latter [8]. Recently, Hayashi et al. pointed out the value of fluid attenuated inversion recovery (FLAIR) MR images as a method for observing leptomeningeal disease [19].

Age-related changes in NCM neuroimaging have been described as a change in the signal intensity associated with a loss of water within the brain as a result of myelinization. Probably the best time to detect the MRI-specific changes is around the 4-month period [16, 41].

The number and size of nevi do not correlate with the amount of melanin deposits within the CNS; however, its distribution along the scalp or in the dorsal midline as well as a large number of satellite nevi in association with a LCMN does increase the risk of CNS involvement [26]. Children with NCM should be evaluated with MRI studies at the earliest time possible, as the lifetime risk for malignancy is currently unknown [14, 26]. Whenever there is a nevus involving the lumbosacral area, additional MRI studies of the spine should be obtained in order to rule out other neural tube defects such as tethering from a lipoma [28].

Taking into consideration how infrequent this disease is, the chemotherapeutic trials have been sparse. Dacarbazine has become the agent of choice for such cases with a response rate in 25% of the patients [24]. Anderson et al. [2] and Falkson [13] have reported rates of 59% response when this antineoplastic agent is administered in combination with cisplatin, BCNU (carmustine), and tamoxifen. However, in NCM patients with active CNS, results have been poor [9, 25]. Nagahiro et al. suggested that monitoring of 5-S-cysteinyldopa in CSF can be a reliable indicator for monitoring the efficacy of chemotherapy as well as progression of the disease within the neuroaxis [29]. Ninety percent of patients in this setting die due to neurologic involvement in the 3 years following initial diagnosis [20]. After the disease has spread to the basal cisterns, convexities, and arachnoid villi, the usual strategy is to shunt the patient to alleviate the symptoms of raised intracranial pressure with some reports of surgical debulking of large lesions [28]. Some authors concerned about the possibility of peritoneal seeding with tumoral cells, recommend the placement of a cell filter along the shunt tract [30]. The differential diagnosis includes the melanotic neuroectodermal tumor of infancy, melanotic nerve sheath tumor (nevus of Ota), and congenital melanocytic nevus [14, 26].