Circumscribed meningeal melanocytic neoplasms: Melanocytoma and melanoma

• Circumscribed meningeal melanocytic neoplasms arise from leptomeningeal melanocytes and range histologically from well-differentiated tumours (meningeal melanocytoma) to frankly malignant neoplasms with aggressive growth properties (meningeal melanoma).

graph LR
  A["Leptomeningeal<br>melanocytes"] --> B["Meningeal melanocytoma"] --> C["Melanocytoma of<br>intermediate grade"] --> D["Meningeal melanoma"]

• Meningeal melanocytomas with increased mitotic activity or invasion of the CNS parenchyma have been defined as melanocytoma of intermediate grade.

• Meningeal melanocytomas and melanomas are rare, accounting for 0.06–0.1% of meningeal tumours.
• Both can occur at any age, but they are most frequent in the fourth and fifth decades of life.

• Meningeal melanocytomas
• Incidence of 1 case per 10 million person-years.
• Slight female predominance: 1.5:1
• Mean age of diagnosis: 45.6 years (range: 23–69 years)

• Meningeal melanomas
• Annual incidence of 0.005 cases per 100 000 population.
• Mean age of diagnosis: 53.7 years (range: 15–86 years)
• The mean age at diagnosis of meningeal melanoma was 48.5 years for adults and 5.4 years (median: 3.0 years) for children.

• Meningeal melanocytoma is generally well-differentiated, reflecting a low-grade lesion, but it is not assigned a WHO CNS grade to melanocytoma itself.

• Meningeal melanomas are frankly malignant neoplasms.

• Tumours with bland histological appearance but increased mitotic activity or invasion of the CNS parenchyma are defined as melanocytoma of intermediate grade.

• Two steps in oncogenesis of meningeal melanocytic tumours not associated with neurocutaneous melanosis.
1. First step: Mutations in GNAQ, GNA11, PLCB4, or CYSLTR2
• GNAQ and GNA11 mutations at codon 209
• are the most frequent, found in about 60–70% of cases.
• Similar to those present in uveal melanoma and blue naevus
• Present in Primary CNS melanomas but much lower fq than melanocytomas.
• These mutations impair GTPase activity, leading to constitutive activation of downstream intracellular pathways, including the RAF/MEK/ERK and Hippo/YAP1 signalling pathways, which regulate cell growth and proliferation.
2. Second step: EIF1AX, SF3B1, or BAP1 mutation
• Higher incidence reported in melanomas.
• BAP1 is a tumour suppressor gene, and loss-of-function hemizygous mutations combined with chromosome 3 monosomy result in decreased or absent BAP1 protein expression.

• Chromosomal changes
• Chromosomal alterations may include
• Gains of chromosome arms 8q and 6p
• Loss of chromosome arms 1p and 6q
• Monosomy of chromosome 3.
• Meningeal melanomas usually have a more complex copy-number variation profile, with multiple large chromosomal gains and/or losses.

• Childhood meningeal melanomas in patients with neurocutaneous melanosis typically harbour NRAS mutations.
• NRAS mutations
• Occurs in
• Cutaneous naevi for adults
• CNS melanocytic neoplasms for children
• If you see there is NRAS mutation in CNS melanocytic neoplasm in adults it is most likely a metastatic lesion
• Involving codon 61
• Not inherited But
• Occurs early in embryogenesis → melanocyte precursors migrate to skin and leptomeninges
• Hence it is Monoclonal

• BRAF V600E mutations
• Occurs in
• Cutaneous naevi of patients with neurocutaneous melanosis (albeit less frequently)
• Does not occur in CNS melanocytic neoplasms

• Tumour progression to melanoma
• Similar to uveal melanoma

Early mutations	Late mutations
GNAQ mutation or GNA11 mutations	BAP1 inactivation or SF3B1 mutation or EIF1AX mutation

• Differentiating primary vs Metastatic disease
• Presence of TERT promoter, NRAS, BRAF, and KIT, are rare in primary CNS melanocytic neoplasms of adults, and when encountered raise suspicion of a metastasis.

• Meningeal melanocytomas
• Extramedullary, intradural compartment at the cervical and thoracic spine.
• Can be dural-based or associated with nerve roots or spinal foramina
• Less frequently, they arise from the leptomeninges in the posterior fossa or supratentorial compartments.
• Trigeminal cave
• A site with a peculiar predilection for primary melanocytic neoplasms, and tumours at this site are associated with an ipsilateral naevus of Ota

• Meningeal melanomas
• may occur throughout the neuraxis, but they show a predilection for the spinal canal and posterior fossa.

• A purely intraparenchymal location of a melanoma in the CNS is highly indicative of metastatic disease.

• Patients mostly present with symptoms related to compression of the spinal cord, cerebellum, or cerebrum by an extra-axial mass, with focal neurological signs depending on location.

• Distant metastasis from meningeal melanocytic tumours, mostly melanomas, are rare (reported in liver, bone, and lungs).

• CT
• Well-defined
• Isodense to hyperdense
• Homogenous
• Contrast enhancing lesion

• MRI
• On MRI, they often show T1 hyperintensity due to the paramagnetic properties of melanin pigment, and they are typically isointense to hypointense on T2-weighted images.
• Meningeal melanocytomas and melanomas are isoattenuating to hyperattenuating, contrast-enhancing on CT, with an imaging appearance similar to that of meningiomas but usually without hyperostosis or intratumoural calcification.
• CNS structures adjacent to a meningeal melanoma are often T2-hyperintense due to vasogenic oedema.
• Variable depending on the amount of melanin content present.
• Signal characteristics include:
• T1: isointense or hyperintense
• T2: isointense or hypointense
• T1 C+ (Gd): heterogeneous enhancement
• T2* GRE: may show blooming of low signal.
Images

• The clinical behaviour correlates with histopathological features.
• Melanocytomas typically lack anaplastic features, but local recurrence or leptomeningeal seeding occur in some patients, with intermediate-grade melanocytic tumours seeming more recurrence prone.

• Malignant transformation of a melanocytoma (Intermediate-grade melanocytic tumours) and metastatic spread outside the CNS have been reported.

• Meningeal melanoma is usually a highly aggressive and radioresistant tumour with a poor prognosis.

• The prognosis tends to be better for patients with primary meningeal melanoma (particularly if complete resection of the primary tumour can be achieved) than for patients with CNS metastasis of cutaneous melanoma.

• Some meningeal melanocytic tumours (EIF1AX, SF3B1, and BAP1 mutations; chromosome 3 monosomy; or complex copy-number variations) show aggressive clinical behaviour.

• The prognosis for NRAS-mutant meningeal melanoma in children is very poor.