General
- Meningeal melanocytosis
- A diffuse or multifocal proliferation of cytologically bland melanocytic cells that
- Arises from the leptomeninges
- Involves the subarachnoid space of the cerebral hemispheres.
- Cells can spread into the perivascular spaces.
- Without frank invasion of the brain.
- Meningeal melanomatosis
- A primary CNS melanoma
- That arises from leptomeningeal melanocytes
- Displays a diffuse pattern of spread throughout the
- Subarachnoid space
- Virchow-Robin spaces
- Often with CNS invasion
Definition
Meningeal Melanocytosis
- Essential:
- Diffuse or multifocal primary meningeal melanocytic neoplasm.
- Absence of CNS parenchyma invasion.
- Absence of marked cytological atypia.
- Absence of mitotic activity.
- Absence of necrosis.
- Desirable:
- In children, often NRAS-mutant and rarely BRAF-mutant.
Meningeal Melanomatosis
- Essential:
- Diffuse or multifocal primary meningeal melanocytic neoplasm.
- Invasion of the CNS parenchyma and/or marked cytological atypia and/or mitotic activity and/or necrosis.
- Desirable:
- In children, often NRAS-mutant and rarely BRAF-mutant.
Epidemiology
- Rare, making population-based incidence difficult to estimate.
- The incidence of neurocutaneous melanosis is reported as 0.5–2 cases per 100,000 person-years.
- Melanocytosis primarily affects children, frequently in the context of neurocutaneous melanosis. It rarely occurs without cutaneous melanocytic lesions.
- Age at presentation for CNS manifestations ranged from stillbirth to the second decade
- Equal sex distribution
- No racial predisposition
- Strongly linked with neurocutaneous melanosis
- Rare phacomatosis (a group of neurocutaneous disorders characterised by involvement of structures that arise from the embryonic ectoderm (thus central nervous system, skin and eyes)) that is typically associated with giant congenital naevi and presents before the age of 2 years
- Melanomatosis has a bimodal age distribution and may become manifest in children (with or without neurocutaneous melanosis) as well as in adults (mostly in the fourth decade of life).
WHO grade
- Meningeal melanocytosis or meningeal melanomatosis does not have a grading.
- Meningeal melanomatosis is described as a very aggressive disease.
Histopathology
Macroscopic
- Dependent on melanin content, these neoplasms may appear as dense black replacement of the subarachnoid space or dusky clouding of the meninges.
- Macroscopic appearance is similar to that of melanoma arising from meningeal melanocytosis, with brownish discolouration of the thickened leptomeninges and black discolouration of the underlying cerebral cortex.
B Macroscopy of meningeal melanomatosis in a child with neurocutaneous melanosis who succumbed at the age of 17 months due to rapid disease progression.
C Macroscopic appearance of the cerebral tissue shows brownish discolouration of the thickened leptomeninges and black discolouration of the underlying cerebral cortex.
Microscopic
- The pathological proliferation of leptomeningeal melanocytes and their production of melanin account for the main microscopic findings in these diseases
Melanocytosis | Melanomatosis |
-No CNS parenchyma invasion -Accumulate within the subarachnoid and Virchow-Robin spaces. | Has CNS parenchyma invasion |
the presence of mitotic activity, severe cytological atypia, or necrosis |
- Tumour cells may assume a variety of shapes, including spindled, round, oval, and cuboidal.
- Distinction from metastasis of cutaneous melanoma may be impossible using microscopy alone.
- Tumour cells often have epithelioid features and immunocytochemically express melanocytic markers, potentially containing melanin pigment.
Immunophenotype
- Positive for melanocytic markers and may contain melanin pigment.
Genetic features
- These tumours are mostly associated with postzygotic somatic mutations in NRAS, considered a first hit in oncogenesis.
- NRAS mutations often occur at codon 61, the catalytic centre of the GTPase, causing constitutive activation of downstream pathways including RAF/MEK/ERK and PI3K/AKT/mTOR, thus promoting proliferation and growth.
- Amplification of the mutated NRAS gene has been described in an aggressive form of neurocutaneous melanosis.
- Copy-number variations in newly acquired or clinicoradiologically progressive diffuse meningeal melanocytic neoplasms show overlap with those described in cutaneous melanoma, even without malignant features at the histopathological level.
Localisation
- These diffuse neoplasms involve large expanses of the leptomeninges/subarachnoid space, potentially with focal or multifocal nodularity.
- Supratentorial leptomeninges
- Infratentorial leptomeninges
- May involve superficial brain parenchyma by extending into perivascular VirchowRobin spaces.
- Sites of highest frequency include the
- Cerebellum
- Pons
- Medulla
- Temporal lobe
- Meningeal melanomatosis frequently invades the CNS parenchyma.
Clinical features
- Due to
- Hydrocephalus
- SAH blockage of CSF due to melanomatosis and melanocytosis overgrowth
- Local effects on the CNS parenchyma.
- Neuropsychiatric symptoms, bowel and bladder dysfunction, and sensory and motor disturbances are common.
- Once malignant transformation occurs, symptoms progress rapidly, with increasing intracranial pressure resulting in irritability, vomiting, lethargy, and seizures.
- Skin effects
- Neurocutaneous melanosis
- = melanocytosis/melanomatosis+giant or numerous congenital melanocytic naevi of the skin,
- Usually involving the trunk/head and neck, and
- With various other malformative lesions, such as Dandy-Walker syndrome, syringomyelia, and lipomas
- Melanocytosis may also be associated with congenital naevus of Ota
- Oculodermal melanosis (Nevus of Ota)
- Aka: oculodermal melanocytosis, oculomucodermal melanocytosis, or congenital melanosis bulbi
- A benign mesodermal melanosis
- Localization
- Distributions of the V1 and V2 with associated hyperpigmentation of the eye and its adnexa.
- Clinical features
25% of patients with meningeal melanocytosis | Have concomitant cutaneous lesions. |
0-15% of patients with large congenital melanocytic naevi of the skin | Have clinical symptoms of CNS melanocytosis |
23% of asymptomatic children with giant congenital naevi | Have radiological evidence of CNS involvement |
Entrapment of melanocytes in the upper third of the dermis leads to gray-blue macular hyperpigmentation of the conjunctiva and sclera and ipsilateral facial skin
Associated features
- Communicating hydrocephalus, arachnoid cysts, syringomyelia, brain tumours (astrocytoma, choroid plexus papilloma, ependymoma, germinoma), and structural defects (Dandy-Walker or Chiari malformations).
Radiological features
- CT and MRI typically show diffuse thickening and enhancement of the leptomeninges, often with focal or multifocal nodularity.
- Depending on melanin content (due to paramagnetic properties), they may appear isodense or hyperintense on T1-weighted images and hypointense on T2-weighted images.
- Melanin has paramagnetic properties
- Melanin has a high affinity for metal ions, especially copper, iron, manganese, and zinc.
- One of melanin's important physiological functions is to serve as a scavenger of free metals and radicals.
A T1-weighted axial MRI revealing a hyperintense, contrast-enhancing lesion outlining the gyri and sulci in the left fronto-parieto-occipital region in a 5-year-old child.
Prognosis
- Melanocytosis may remain asymptomatic for a variable period of time, but once symptoms develop, the prognosis is usually poor.
- Melanomatosis is typically a very aggressive disease with a dismal prognosis.
- The prognosis for NRAS-mutant meningeal melanoma and melanomatosis in children is very poor.
- Distinction from metastatic spread derived from an extradural (usually cutaneous) melanoma is critical for prognostication and therapy.
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