Neurocutaneous Melanosis (Neurocutaneous melanocytosis)

Are You Confident of the Diagnosis?

Neurocutaneous melanosis (NCM) is a rare congenital syndrome characterized by the presence of congenital melanocytic nevi and melanosis within the central nervous system, most commonly involving leptomeninges but in some cases involving the brain parenchyma. NCM is present at birth and is not the result of metastatic spread from a primary cutaneous melanoma. It may be asymptomatic or (in a minority of patients) cause neurologic signs and symptoms even resulting in death due to either malignant change (ie, melanoma) or space-occupying effects from the proliferation of “benign” melanocytes within the closed space of the central nervous system.

Characteristic findings on physical examination

The diagnosis of NCM should be considered in any neonate or child who has a large cutaneous melanocytic nevus (typically defined as one that is projected to be greater then 20 cm in largest diameter in adulthood: (Figure 1). NCM can also occur in the setting of multiple (>3) congenital melanocytic nevi without the presence of a large or giant nevus.

Figure 1.

Clinical suspicion for NCM increases if there are multiple “satellite” nevi or if neurologic signs or symptoms are present in the setting of a large congenital melanocytic nevus. In most cases, the large melanocytic nevi involved in the setting of NCM are located in a “bathing trunk” or occipital/cervical, “cape-like” distribution (Figure 2) . Posterior axial location is an additional risk factor for NCM (Figure 3). An increased number of satellite nevi is more predictive of NCM risk than size or location (Figure 4, Figure 5) and multiple intermediate sized congenital nevi (>3) may convey higher risk then the presence of one large CMN (Figure 6).

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

The “melanosis” that occurs in NCM refers to an excess of melanotic cells in the meninges that may be nodular or diffuse. This melanosis occurs in the locations of the brain or spinal cord that may have macroscopic pigmentation normally. These sites include the convexities or base of the brain, ventral surfaces of the pons, medulla, and upper cervical or lumbosacral spinal cord. It is the extent of melanocytic infiltration by these normally quiescent melanocytic cells that is pathologic. Mass effects related to the proliferation of these cells can lead to the clinical complications of NCM.

Based on the presence or absence of clinical signs and/or symptoms, NCM can be divided into asymptomatic and symptomatic forms. The prognosis for symptomatic NCM is poor. The prognosis for asymptomatic patients (whose NCM is usually discovered through screening) is difficult to predict, but likely analogous to cutaneous disease in that only a minority of patients will go on to develop progressive CNS disease (eg, melanoma or proliferation leading to symptoms).

Neurologic symptoms are usually present within the first 5 years of life and most often occur before 2 years of age, with approximately 50% of patients who have central nervous system-related clinical manifestations presenting within the first year of life. Rarely symptoms can present in the second or even third decade of life.

Symptoms of NCM in infants are usually related to increased intracranial pressure due to mass effect on the ventricular flows, which can result in hydrocephalus, seizures, cranial nerve palsy (particularly related to cranial nerve VI). More general signs and symptoms of increased intracranial pressure include irritability, lethargy, headache, recurrent vomiting, generalized seizures, increased head circumference, bulging anterior fontanelle, photophobia, papilledema and neck stiffness. Physicians should monitor for changes head circumference or other signs/symptoms of increased intracranial pressure in NCM patients regularly in infancy and early childhood. More subtle presentations can occur as well, so patients who are found to have NCM when screening is done should have a baseline evaluation and regular follow up by neurology. In one study the authors described mild to minimal motor deficits, nerve dysfunction and impaired mental status in patients thought to be asymptomatic before thorough examination.

In a patient with known NCM, any new onset neurologic sign or symptom must be investigated thoroughly. Evaluations should include repeat magnetic resonance imaging (MRI) with contrast (contrast is not usually necessary for baseline studies to establish the diagnosis but is to evaluate new symptoms), and evaluation of cerebrospinal fluid (CSF) fluid via lumbar puncture. Findings in the CSF in this setting typically include an elevated protein level with normal glucose and a sterile leukocytosis. A yellow discoloration of the CSF may occur secondary to melanin granules; and the CSF in patients with NCM may even reveal melanoctyes of a benign, or in the setting of NCM related melanoma, malignant nature.

Structural abnormalities of the central nervous system (CNS) can also be associated NCM and can even be detected on prenatal ultrasound. Several patients with NCM have been reported to have the Dandy Walker complex. Other associated malformations of the CNS are discussed below. Patients manifesting structural abnormalities in association with NCM are more likely to become symptomatic.

A subset of NCM patients becomes symptomatic later in childhood. Often this occurs around 7-10 years of age or early in puberty. This subset of patients often tend to have symptoms and signs associated with intracranial mass lesions and spinal cord compression; they may exhibit psychiatric symptoms, expressive aphasia, dysarthria, focal seizures, paraplegia or localizing sensorimotor changes. Physicians should screen for these symptoms in older NCM patients as well, as there are rare reports of patients who do not manifest NCM related symptoms until the second or third decades

The onset of neurologic symptoms can also serve as a “red flag” indicating the development of CNS melanoma, which underlies approximately half of cases of overtly symptomatic NCM. In this setting, the clinician should consider also consider the possibility of metastasis from a primary cutaneous melanoma. Any worrisome skin findings; in particular new, firm subcutaneous nodules or ulcerated papules or nodules within CMN; should be biopsied for histologic evaluation.

However, the weight of evidence suggests that, in patients with LCMN and NCM, symptomatic CNS disease stemming from NCM in the brain is a much more common morbidity then the development of primary cutaneous melanomas. Cutaneous melanoma is rare even in large or giant CMN. It is exceedingly rare in small or intermediate congenital melanocytic nevi. Most melanomas that manifest within this setting occur within the LCMN (not in satellites) and at an early age (in one retrospective study 89% of melanomas in LCMN occurred before the age of 30)

Expected results of diagnostic studies

The diagnosis of NCM in a patient with CMN is typically made via MRI of the brain and spinal cord (Figure 7).

Figure 7.

When screening for NCM in an asymptomatic patient, the study can be done without contrast for evaluation of the brain and spinal cord. However, in older patients whose brain have undergone myelinization (occurs around 4-5 months), contrast may help visualize areas of melanosis. The most characteristic findings of NCM on MR imaging are focal T1 or T2 shortening that correlates with increased melanization. It is thought that the presence of melanin elicits paramagnetic effects, shortening the T1 or T2 relaxation times.

The most common locations for this leptomeningeal melanosis include the anterior temporal lobes in the region of the amygdala, the base of the brain, the interpeduncular fossa, the ventral surface of the pons, the medulla and the cerebellum, the upper cervical spinal cord and the ventral lumbosacral cord . Involvement of the spinal meninges in NCM has been reported in as many as 20% of cases. A rare presentation is that of diffuse leptomeningeal enhancement in postgadolinium T1-weighted MR imaging of the convexities of the cerebral and cerebellar hemispheres, posterior surface of the brainstem, and quadrigeminal and superior vermian cisterns that may also be seen.

When evaluating a symptomatic known or suspected NCM patients with symptoms, contrast should be administered. Vasogenic edema and areas of hemorrhage or necrosis may indicate malignancy. Electroencephalographic studies often demonstrate either focal or generalized abnormalities. Various other imaging techniques such as computed tomography with contrast can show leptomeningeal involvement. However, it is generally agreed that MR imaging is the most sensitive modality to detect neural melanosis as well as intra-cerebral and extra-cerebral tumors in NCM. It is also the diagnostic procedure of choice in the evaluation of hydrocephalus.

Histologically, the cutaneous lesions in NCM are no different than other congenital melanocytic nevi. Most are intradermal melanocytic nevi with about a third showing features of compound nevi. The nevus cells often extend into the reticular dermis and occasionally into the subcutis with nevus present between collagen bundles, around appendages, nerves and blood vessels. As discussed below in the “Systemic Complications and Implications” section, there are some histologic features of the CNS lesions that make it difficult to determine whether melanocytes in the CNS are benign or malignant; but several distinguishing features do exist. If feasible, biopsy of CNS melanocytic tumors, or histologic examination of melanocytes culled from the CSF can help determine the biologic behavior of new or symptomatic tumors.

The issue of how, whe, and which patients should be screened for NCM is a controversial one, discussed further in the “Management” section of this chapter. The main rationale for this type of screening is to try to provide patients and families with prognostic information. While it is appropriate to alert families to the possibility that a child with large or multiple congenital nevi might have CNS or spinal cord melanosis, it is important to reassure them that the association is actually quite rare. Also, it is important to convey that though the outcome in patients with symptomatic NCM is very poor, most patients with MRI-documented NCM are asymptomatic and remain so.

Who is at Risk for Developing this Disease?

Patients with large congenital nevi (LCMN) are at risk for neurocutaneous melanosis. A “large” congenital nevus is a nevus that is estimated to become (by adulthood) equal to or greater than 20 cm in its largest diameter. Neurocutaneous melanosis seems to occur in about 2.5-7% of patients with LCMN overall, but the exact risk of NCM in patients with LCMN is really unknown at this time. Patients are at increased risk if they have LCMN with multiple satellite lesions, or in posterior axial locations.

Multiple nevi are also important. Perhaps a third of cases of NCM occur in a setting of multiple small or intermediate sized nevi in the absence of any LCMN. NCM has almost never been reported in patients with less then three CMN. It appears that in patients with LCMN, the risk of NCM increases as the number of satellites increase. This is in contrast to the risk of cutaneous melanoma, which increases with the size of the CMN but is not related to the number of satellites.

The risk of NCM in patients with large cutaneous melanocytic nevi (LCMN) may actually be greater then the risk that these patients will develop cutaneous melanomas. In patients with large congenital melanocytic nevi that involve the posterior axis and have multiple satellite nevi, studies have shown that approximately 20-30% of these “high risk” patients will have asymptomatic NCM when screened with MRI.

Neurocutaneous melanosis is not a hereditary condition. It is sporadic and occurs equally between the sexes. It is thought to be more common in Caucasians than African-Americans, but detailed studies on the ethnic distribution of this disease are not available at this time.

What is the Cause of the Disease?

Etiology

During embryogenesis, melanoblasts normally migrate from the neural crest, along the leptomeninges and then to the skin. It is thought that aberrant migration of these cells results in the deposition of melanocytes within and along the leptomeninges. The benign proliferation of melanocytes in and around the leptomeninges can result in increased intracranial pressure leading to neurologic signs and symptoms. The malignant proliferation of these melanocytes can result in primary melanoma occurring within the central nervous system.

Pathophysiology

The reason for the aberrant migration of early melanotic cells is not well understood. However, some studies indicate that alteration of Met receptor signaling in neural crest -derived melanocytes may be involved. Hepatocyte growth factor/scatter factor (HGF/SF) binding to Met receptors is intimately involved in proliferation, motility and melanin synthesis in vitro. A mouse model with overexpression of HGF/SF exhibits both pigmented nevi and leptomeningeal melanocytosis.

Systemic Implications and Complications

Patients manifesting asymptomatic NCM by definition do not have systemic complications and do quite well. On the other hand, the prognosis for patients with symptomatic NCM is quite poor. Median survival time after the onset of symptoms has been estimated at around 6.5 months. Due to the young age at which most NCM patients present with clinical symptoms, the median age of death is approximately 4.5 years old.

Death can occur from a variety of complications; most commonly, increased intracranial pressure, hydrocephephalus, and brainstem compression. For symptomatic patients, an honest and forthright discussion of prognosis is an important aspect of management; particularly in the case of infants. That being said, there are patients with symptomatic NCM whose symptoms can be controlled or at least mitigated with anti-seizure medications, surgical or other interventions for many years.

Dandy-Walker complex and other CNS structural abnormalities, such as posterior fossae cysts, syringomyelia, arachnoid cysts, intraspinal lipomas, and defects of the vertebrae or skull have been described in patients with NCM and likely portend a greater likelihood of developing symptomatic NCM. The pathogenic mechanism of this association is unknown but may be related to defective ectodermal-mesodermal interactions secondary to excessive meningeal melanosis, leading to maldevelopment. In cases of children with symptomatic NCM and an associated Dandy Walker complex, the majority of reported patients have died before the age of 4 and the prognosis is even worse then that of symptomatic NCM alone.

Hydrocephalus is the most common complication of NCM and affects approximately two-thirds of symptomatic patients. Many patients die due to complications secondary to increased intracranial pressure. Most often the hydrocephalus is of the “communicating” type; which occurs when the accumulation of melanotic cells at the basal subarachnoid cisterns obstructs CSF flow and decreases the reabsorption of CSF in the arachnoid villi. A smaller proportion of NCM related hydrocephalus is of the “noncommunicating” type related to the obstruction of outflow foramina or aquaductal stenosis by melanotic cells.

Leptomeningeal melanoma, occurring most frequently in the frontal and temporal lobes, is a feared complication of NCM and occurs in approximately half of all patients with symptomatic NCM. However, it may also be an overdiagnosed entity in NCM patients. In the setting of NCM; it is difficult to differentiate benign from malignant lesions due to the marked cellular pleomorphism, tendency towards nesting and the appearance of invasion due to close approximation into endothelial spaces that characterizes the “benign” melanotic cells found in the meninges of NCM patients.

Histologic features that help identify leptomeningeal melanoma include: (1) necrosis and hemorrhage (2) invasion of the actual basal lamina of the endothelium (3) increased degree of cellular atypia and mitotic activity (4) the presence of annulate lamellae (concentric lamellar structures thought to represent modified melanosomes). If biopsy of nodules suspicious for malignant degeneration proves impossible or undesirable to the patient due to risk of neurologic damage, postitron emissions tomography may be useful in assessing the potential biologic behavior of new or changing CNS lesions.

Unfortunately, the differentiation between benign and malignant leptomeningeal tumors may be of more academic than prognostic value. The outcomes for symptomatic neurocutaneous melanosis with and without the complication of leptomeningeal melanoma are similarly bleak although some studies do show worse prognosis in the presence of leptomeningeal melanoma.

Treatment Options

Treatment options are summarized in Table I.