Primary melanocytic tumors of the central nervous system: a review with focus on molecular aspects

Abstract

Primary melanocytic tumors of the central nervous system (CNS) represent a spectrum of rare tumors. They can be benign or malignant and occur in adults as well as in children, the latter often in the context of neurocutaneous melanosis. Until recently, the genetic alterations in these tumors were largely unknown. This is in contrast with cutaneous and uveal melanomas, which are known to harbor distinct oncogenic mutations that can be used as targets for treatment with small-molecule inhibitors in the advanced setting. Recently, novel insights in the molecular alterations underlying primary melanocytic tumors of the CNS were obtained, including different oncogenic mutations in tumors in adult patients (especially GNAQ, GNA11) vs. children (especially NRAS). In this review, the focus is on molecular characteristics of primary melanocytic tumors of the CNS. We summarize what is known about their genetic alterations and discuss implications for pathogenesis and differential diagnosis with other pigmented tumors in or around the CNS. Finally, new therapeutic options with targeted therapy are discussed.

Keywords: GNA11; GNAQ; NRAS; brain; central nervous system; leptomeningeal melanocytic neoplasms; melanocytoma; melanoma; melanotic schwannoma; metastasis; molecular; mosaic RASopathy; neurocutaneous melanosis.

Figure 1

Origin and morphology of leptomeningeal melanocytes. A. Melanoblasts, the precursors of melanocytes, are derived from the neural crest early during embryogenesis and undergo migration to reach their destination in cutaneous and extra‐cutaneous locations, the latter including mucosal surfaces, uveal tract, inner ear and leptomeninges (arrows). At the center, an incomplete cross‐section of a human embryo is depicted showing neural crest cells that detach from the tips of the neural folds just before or shortly after they fuse to give rise to the neural tube. These multipotent NC cells, represented by black dots, yield melanoblasts that become spatially and temporally segregated from other NC‐derived cell types. B,C. Melanocytes can be found especially around the upper part of the cervical spinal cord and may cause a grayish hue (arrow in panel C). D. Microscopically, these leptomeningeal melanocytes are slender, elongated, and darkly pigmented cells (arrow). NC = neural crest cells; NT = neural tube.

Figure 2

Main intracellular pathways implicated in different subtypes of melanoma. Mutations in KIT are relatively frequent in mucosal melanoma (mucm, ∼20%), result in activation of the MAPK and PI3/AKT/mTOR pathways, and can be treated with KIT inhibitors. Approximately 50% of CM harbor mutations in BRAF^V600, which provide a therapeutic target for selective BRAF inhibitors. Mutations in NRAS (∼20% of CM) signal to MEK/ERK through CRAF, but also to the PI3/AKT/mTOR pathway. MEK inhibitors have shown activity in some patients with NRAS mutant melanoma. Signaling pathways downstream of GNAQ/GNA11 (∼80% of UM) include activation of PKC through the release of diacylglycerol (DAG) by β‐PLC, which can activate the MAPK pathway. Another downstream pathway is the Hippo‐YAP pathway resulting in activation and translocation of the transcriptional coactivator YAP into the nucleus through a mechanism of actin polymerization regulated by the GTPases Rho and Rac. Metastatic UMs frequently harbor inactivating mutations in BAP1, which is involved in multiple functions including regulation of the cell cycle and epigenetic modulation. Inhibition of downstream components such as MEK, PKC, BAP1 and YAP are now under (pre) clinical investigation for treatment of GNAQ/GNA11‐mutated UM. CM = cutaneous melanoma; MAPK = mitogen‐activated protein kinase; MucM = mucosal melanoma; PKC = protein kinase C; PLC = phospholipase C; UM = uveal melanoma; ERK = extracellular signal‐regulated kinase; MEK = mitogen‐activated ERK kinase; PI3K/AKT/mTOR = phosphatidylinositol 3‐kinase/protein kinase AKT/mammalian target of rapamycin.

Figure 3

Relative frequency of oncogenic mutations in primary LMNs in adults vs. uveal and cutaneous melanomas. Primary leptomeningeal melanocytic neoplasms (LMNs) in adults frequently harbor oncogenic mutations in GNAQ and to a lesser extent in GNA11. The mutation profile is comparable with that of uveal melanoma, but distinct from cutaneous melanoma. GNAQ/GNA11/BRAF mutation analysis can be used as a diagnostic tool in the differential diagnosis of primary LMNs vs. metastasis of cutaneous melanoma to the central nervous system (CNS). The mutation frequencies depicted are based on the studies summarized in Table 3.

Figure 4

Example of the diagnostic potential of molecular analysis in a patient with a pigmented tumor around the spinal cord. A 62‐year‐old man presented with neurologic symptoms consistent with myelopathy at the thoracic level. Magnetic resonance imaging showed an intra‐ and extramedullary spinal tumor at thoracic levels 7–9 and the lesion was resected. Histology revealed a cellular tumor with a mixture of spindle and epithelioid cells, arranged in nests and sheets, and with oval nuclei with prominent nucleolus and moderate to strong nuclear atypia. Focally, melanin pigment was present. (A) Proliferation activity was limited (three mitoses per 10 high‐power fields, arrow in B; MIB‐1 labeling index around 5%) and necrosis was absent. The tumor showed invasion in CNS tissue. In the reticulin stain (Laquesse), nests of tumor cells rather than individual tumor cells were encircled by reticulin fibers, indicating melanocytic rather than schwannian differentiation (C). Tumor cells were strongly reactive with Melan‐A (D) and HMB‐45. Based on histology and knowing that the patient did not have a (history of) cutaneous melanoma, a diagnosis of primary leptomeningeal melanoma was made. Indeed, mutation analysis of the hotspot regions of GNAQ, GNA11, BRAF, NRAS and KIT revealed a GNAQ^Q209L mutation {c.626A > T[p.(Gln209Leu)]}, fully supporting the diagnosis of a primary melanocytic tumor of the CNS over a metastatic cutaneous melanoma or melanotic schwannoma (E, forward sequence, mutation area is marked as a red column). Of note, metastatic uveal melanoma and malignant blue nevus still needs to be in the differential diagnosis in case of a GNAQ‐mutated melanocytic tumor in/around the CNS, but these options were ruled out in our patient as well. CNS = central nervous system

Figure 5

Acquisition of somatic NRAS mutations early during embryogenesis underlies the pathogenesis of  NCM. Neural crest cells are a multipotent population of cells that arise early during embryogenesis; they give rise to diverse cell lineages including melanocytes (depicted at the left: neural crest cells are represented by black dots in cross‐section of human embryo). Early acquisition of a post‐zygotic, somatic NRAS mutation is thought to underlie the pathogenesis of NCM: one of the neural crest cell‐derived precursor cells acquires an NRAS mutation and gives rise to a mosaic pattern of NRAS‐mutated cells that further migrate and colonize the skin and/or leptomeninges. The timing of acquisition of the mutation in the precursor cell is then a co‐determinant for the resulting phenotype. NC = neural crest cells; NCM = neurocutaneous melanosis; CMN = congenital melanocytic nevus; LMN = leptomeningeal melanocytic neoplasm.