Melanocytic tumors involving the CNS

2024-12-09 Paola Dal Cin, PhD , Scott Ryall, PhD Affiliation

1.Brigham and Women's Hospital , Harvard Medical School, Boston , MA (USA)
2.Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)

Keywords

Primary meningeal melanocytic tumors ,melanocytosis, melanomatosis

Classification

Definition

Primary meningeal melanocytic tumors encompass a spectrum of ultra-rare diagnostic entities that may be diffuse or circumscribed and benign or malignant. When circumscribed, tumors are collectively referred to as meningeal melanocytomas if benign and meningeal melanomas if malignant. Of note, meningeal melanocytomas with elevated mitotic activity and/or invasion of the central nervous system (CNS) parenchyma are considered intermediate grade. In contrast, diffuse meningeal melanocytic tumors, characterized by their involvement in the subarachnoid space, are referred to as melanocytosis and melanomatosis when benign and malignant, respectively. Both adults and children can be affected by these neoplasms, the latter often in the context of neurocutaneous melanosis. OMIM:249400^1,2

Genetic analysis is particularly helpful in establishing the diagnosis of a primary melanocytic tumor from other melanotic CNS tumors. Evaluation of GNAQ, GNA11, PLCB4, and CYSLTR2 is pertinent for this distinction. Identification of additional SF3B1, EIF1AX, or BAP1 alterations in the presence of complex copy number variations indicates an aggressive course most consistent with meningeal melanoma regardless of the underlying histological features. ³ In children, NRAS, and rarely BRAF, mutations are typical in both circumscribed and diffuse primary melanocytic tumors. ⁴

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Melanocytic tumors involving CNS	Genetic marker(s)
Diffuse meningeal melanomatosis and melanocytosis	Meningeal melanomatosis and melanocytosis are most commonly associated with activating mutations at the NRAS hotspot p.Q61 resulting in consitutive activation of the RAF/MEK/ERK and/or PI3K/AKT/mTOR pathways resulting in dysregulated cell growth and proliferation. ^1,5,6These mutations are more commonly seen in children in association with neurocutaneous melanosis OMIM:249400. These NRAS mutations are thought to be the initiating event in a multistep process that typically involves the acquisition of secondary mutations in TP53 and/or BRAF or amplifcation of the mutated NRAS allele. ^4,7 DNA methylation profiling has proved valuable in disciminating these lesions from other pigmented CNA tumors. ⁸
Circumscribed melanocytoma and melanoma	Circumscribed melanocytoma and melanoma often harbor mutually exclusive acitivating mutations in GNAQ, GNA11, PLCB4, or CYSLTR2, with GNAQ and GNA11 mutations being the most common at 60-70% of cases. ^9-13 Additional alterations in EIF1AX, SF3B1, or BAP1 are most often indicative of an intermediate grade melanocytoma or meningeal melanoma. ^11,13,14 Copy number aberrations in these tumors are rare, but may include 6p and 8q gains, 1p and 6q losses, or monosomy of chromsome 3. ^13,15 Differentiating melanocytoma from melanoma is that the latter typically have a more complex copy-number profile in addition to the aforementioned event .^13,15 These tumors do not harbor mutations in HRAS, KRAS, BRAF, or KIT and have ararely been shown to harbor TERT promoter mutations. ^8,9,16-18 In children, meningeal melanomas typically harbor NRAS mutations in accordance with an underlying neurocutaneous melanosis diagnosis. ^5,6 DNA methylation profiling has proved valuable in disciminating these lesions from other pigmented CNA tumors. ⁸

Article Bibliography

Reference Number	Pubmed ID	Last Year	Title	Authors
1	25534128	2015	Primary melanocytic tumors of the central nervous system: a review with focus on molecular aspects.	Küsters-Vandevelde HV et al
2	39061148	2024	Primary Meningeal Melanocytic Tumors of the Central Nervous System: A Review from the Ultra-Rare Brain Tumors Task Force of the European Network for Rare Cancers (EURACAN).	Pellerino A et al
3	27988846	2017	Copy number variations as potential diagnostic and prognostic markers for CNS melanocytic neoplasms in neurocutaneous melanosis.	van Engen-van Grunsven AC et al
4	25490715	2015	BRAF mutations are also associated with neurocutaneous melanocytosis and large/giant congenital melanocytic nevi.	Salgado CM et al
5	23392294	2013	Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS.	Kinsler VA et al
6	23303902	2013	Primary melanoma of the CNS in children is driven by congenital expression of oncogenic NRAS in melanocytes.	Pedersen M et al
7	26266759	2015	Amplification of mutated NRAS leading to congenital melanoma in neurocutaneous melanocytosis.	Salgado CM et al
8	25399693	2015	Melanotic tumors of the nervous system are characterized by distinct mutational, chromosomal and epigenomic profiles.	Koelsche C et al
9	19936769	2010	Activating mutations of the GNAQ gene: a frequent event in primary melanocytic neoplasms of the central nervous system.	Küsters-Vandevelde HV et al
10	22307269	2012	GNAQ and GNA11 mutations in melanocytomas of the central nervous system.	Murali R et al
11	26744134	2016	Targeted next generation sequencing reveals unique mutation profile of primary melanocytic tumors of the central nervous system.	van de Nes J et al
12	28499758	2017	Activating CYSLTR2 and PLCB4 Mutations in Primary Leptomeningeal Melanocytic Tumors.	van de Nes JAP et al
13	29891723	2018	Integrated Genomic Classification of Melanocytic Tumors of the Central Nervous System Using Mutation Analysis, Copy Number Alterations, and DNA Methylation Profiling.	Griewank KG et al
14	26769193	2016	SF3B1 and EIF1AX mutations occur in primary leptomeningeal melanocytic neoplasms; yet another similarity to uveal melanomas.	Küsters-Vandevelde HV et al
15	25315378	2015	Mutations in g protein encoding genes and chromosomal alterations in primary leptomeningeal melanocytic neoplasms.	Küsters-Vandevelde HV et al
16	22758774	2013	GNA11 and N-RAS mutations: alternatives for MAPK pathway activating GNAQ mutations in primary melanocytic tumours of the central nervous system.	Gessi M et al
17	23683178	2013	Melanocytomas of the central nervous system: a clinicopathological and molecular study.	Wang H et al
18	24645797	2014	Absence of TERT promoter mutations in primary melanocytic tumours of the central nervous system.	Gessi M et al

External Links

Citation

Paola Dal Cin ; Scott Ryall

Melanocytic tumors involving the CNS

Atlas Genet Cytogenet Oncol Haematol. 2024-12-09

Online version: http://atlasgeneticsoncology.org/solid-tumor/209304