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.

Introduction

Primary melanocytic tumors of the central nervous system (CNS) represent a spectrum of rare neoplasms including benign and malignant tumors. They can be circumscribed tumors or diffuse lesions that expand along the leptomeninges. Both adults and children can be affected, the latter often in the context of neurocutaneous melanosis (NCM) 17.

Like other melanocytic neoplasms, primary melanocytic tumors of the CNS are derived from melanocytes that originate from the neural crest early during embryogenesis 80. Precursors of melanocytes, so‐called melanoblasts, migrate during embryonic development mainly via the dorsolateral route and travel to the skin in the first trimester of gestation 34, 63, 94. Most melanoblasts first reach the dermis and subsequently the epidermis that starts to become populated around week 7 in the human embryo 57, 94. Smaller numbers of melanoblasts travel to mucosal surfaces of for example, the aerodigestive and urogenital tract, to the inner ear, the uvea and to the leptomeninges (Figure 1A) 93.

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.

Melanocytic neoplasms can therefore arise in cutaneous as well as in extra‐cutaneous localizations, although the latter is much less frequent. The primary function of melanin pigment is protection against the adverse effects of sunlight, but its function in ultraviolet‐protected locations is less clear 93. It has been suggested that leptomeningeal melanocytes capture toxic cations and free radical species from the blood circulation 129.

The highest concentration of melanocytes in the leptomeninges is usually found at the ventro‐lateral surfaces of the medulla oblongata and around the upper part of the spinal cord 47. Macroscopically, they may cause a grayish hue of the leptomeninges (Figure 1B–D).

As primary melanocytic tumors of the CNS are thought to arise from leptomeningeal melanocytes, we will refer to them as primary leptomeningeal melanocytic neoplasms (LMNs). The first report of such tumors dates from 1859 by Virchow in which he described autopsy findings of a male adult with diffuse leptomeningeal melanocytosis 135. Since that time, their diagnosis, especially the differential diagnosis with metastastic melanoma and with other (partly) pigmented primary CNS tumors, remained a challenge for both clinicians and pathologists.

In the past decade, much has been learned about the genetic alterations in distinct subtypes of melanomas 31, 141. A milestone was the discovery of oncogenic mutations in the BRAF gene in about 50% of cutaneous melanomas 32. This finding led to successful targeted therapy with BRAF inhibitors for patients with metastatic BRAF^V600‐mutated melanoma 24. These developments evoked increased interest in molecular subclassification of especially cutaneous and uveal melanoma. However, for some time, the genetic background of primary LMNs remained largely unexplored, probably because these tumors are rare and it is difficult to assemble larger series.

In this review, we focus on recently obtained insights in the molecular alterations in primary melanocytic neoplasms of the CNS, and we discuss implications for pathogenesis, differential diagnosis and potential targeted therapy. Prior, main clinical and pathologic characteristics of these tumors are briefly addressed.

Main Clinicopathologic Features of Primary LMNs

Classification

According to the present (ie, 2007) World Health Organization (WHO) classification of tumors of the CNS, proliferation of melanocytes in the leptomeninges may give rise to circumscribed or diffuse neoplasms that can either be benign or malignant. Primary leptomeningeal melanomas may arise de novo or by transformation from a non‐malignant precursor. Circumscribed LMNs include melanocytoma (benign) and melanoma (malignant), with in‐between lesions histologically showing features of intermediate‐grade malignancy. Diffuse melanocytic proliferations in the leptomeninges include melanocytosis and melanomatosis and are characterized by diffuse growth of cytologically benign and malignant melanocytic cells, respectively (Table 1) 17.

Table 1.

World Health Organization (WHO) 2007 classification of primary leptomeningeal melanocytic neoplasms. Abbreviation: NCM = neurocutaneous melanosis

	WHO 2007 Primary leptomeningeal melanocytic neoplasms
Circumscribed
	Melanocytoma	Benign/low‐grade	Mostly in adults (de novo)
	Intermediate‐grade melanocytic tumor	Intermediate‐grade
	Melanoma	Frankly malignant
Diffuse
	Melanocytosis	Cytologically benign	Mostly in children (often in the context of NCM)
	Melanomatosis*	Malignant

The distinction between adults and children is not always strict, as cases of circumscribed leptomeningeal melanoma has been described in children with NCM, and melanomatosis* may also become manifest in adults, mostly in the fourth decade 103, 105, 124. Moreover, adult patients can still have a congenital background of their disease, and it is not clear whether all leptomeningeal melanocytic neoplasms in children are congenital in origin.

Circumscribed primary LMNs mostly occur in adults. Children more often present with diffuse leptomeningeal proliferations, often in the context of the congenital syndrome NCM with large and/or multiple congenital melanocytic nevi in the skin. However, diffuse leptomeningeal melanocytosis and melanomatosis may also occur in adult patients 8, 89, 100, 105, 124 while circumscribed primary leptomeningeal melanoma has been described in children 70, 84, 103. Benign and malignant primary LMNs can be associated with other melanocytic skin lesions such as blue nevi and nevi of Ota (or oculo‐cutaneous melanosis if the eye is involved) 2, 10, 65, 95.

Circumscribed neoplasms

Melanocytoma

Melanocytoma is generally a slow‐growing neoplasm with a peak incidence in the fifth decade and a slight predilection for women. It has an estimated incidence of 1 per 10 million per year 17. Melanocytoma occurs especially in the cervical and thoracic spinal region, the posterior cranial fossa and Meckle's cave, which is probably related to the higher density of melanocytes in the normal leptomeninges at these sites (Table 2) 17.

Table 2.

Main clinicopathologic features of primary leptomeningeal melanocytic neoplasms. Abbreviations: CNS = central nervous system; LMNs = leptomeningeal melanocytic neoplasms; NCM = neurocutaneous melanosis

		Incidence	Sex, age	Localization	Behavior/prognosis	Treatment
Circumscribed LMNs	Melanocytoma	1/107/year 17	F > M (1.5:1) median; 45–50 years 17	Spinal region (cervical, thoracic)**; posterior fossa; Meckel's cave 17	Frequent local recurrence, esp. in case of incomplete resection*** 108; malignant transformation rare 72, 132	Complete resection if possible. Radiation therapy in case of incomplete resection or recurrence 108
	Melanoma	0.5–0.9/107/year 14, 17, 54	M > F median; 4 years 17	Along the neuroaxis, slight predilection for spinal cord and posterior fossa 17	Distant metastases rare 72; better prognosis in case of complete resection compared with CNS melanoma metastasis 113, 123	Complete resection if possible, postoperative radiotherapy is recommended 113; usefulness of chemotherapy is not established 124
Diffuse LMNs	Melanocytosis	Very rare*	Children, mostly in context of NCM, rarely without cutaneous melanocytic lesions 17, 18	Supra‐ and/or infratentorial/spinal leptomeninges; most frequent in/near cerebellum, pons, medulla and temporal lobes 17	Poor prognosis, once symptomatic 65	Efficacy of chemotherapy and radiotherapy is not established. Chemotherapy might show some benefit 90.
	Melanomatosis	Very rare*	Bimodal distribution: children, mostly in context of NCM or adults, fourth decade 3, 105	Supra‐ and/or infratentorial/spinal leptomeninges, and/or superficial brain parenchyma 17	Dismal prognosis 3, 105	Not established. Chemotherapy and radiotherapy was reported to have benefit in a NCM patient with melanomatosis 127.

*Population‐based incidence is not available 17.

**Mostly in the extramedullary, intradural compartment of the spinal canal.

***The biologic behavior of intermediate‐grade melanocytomas is variable.

While most melanocytomas are intradural, extramedullary tumors, occasionally intramedullary or paraspinal cases have been reported 39, 97. Melanocytomas contain variable amounts of melanin pigment and may macroscopically appear black, red‐brown or blue, and even amelanotic 17. The unique paramagnetic properties of melanin result in a fairly characteristic isointensity to hyperintensity on T1‐weighted magnetic resonance imaging (MRI) and iso‐or hypointensity on T2‐weighted images 124. Symptoms are related to their location and include myelopathy, radiculopathy, cranial nerve deficiency, seizures and hydrocephalus 124. Especially in case of incomplete resection, melanocytomas frequently recur (up to 50% recurrence reported 1 year after surgery) 108. Also, aggressive behavior with leptomeningeal seeding or rarely malignant transformation into melanoma has been reported 20, 72, 108, 132. Whenever possible, melanocytomas should be completely resected. In case of incomplete resection or recurrence adjuvant radiation therapy is advised 108.

Histologically, melanocytomas consist of variably pigmented, well‐differentiated melanocytes showing little cytonuclear atypia and low proliferative activity [zero to one mitosis per 10 high‐power fields (HPFs) and MIB‐1 labeling index (LI) < 1%–2%] 16, 17. At present, histologic features that reliably predict more aggressive behavior are lacking.

Melanoma

Circumscribed primary melanoma of the leptomeninges occurs along the neuroaxis with a slight predilection for the spinal cord and posterior fossa. It most frequently occurs in adults, particularly men, with a peak incidence in the fifth decade (Table 2) 14, 17. Reported incidences vary between 0.5 and 0.9 per 10 million per year, but this is likely an underestimation because of under‐recognition 14, 54. Distant metastases from a primary leptomeningeal melanoma are rare and have been reported in the liver, bones and lungs 14, 72, 75, 138. Prognosis is variable and several studies have reported a better prognosis compared with metastatic melanoma to the CNS with long‐term survival up to 12 years in case of localized disease and complete resection 49, 110, 113. Whether cases with prolonged survival may have been in fact cases that would now meet the criteria of melanocytomas or intermediate‐grade lesions is unclear.

Melanocytoma of intermediate‐grade malignancy

Unequivocal classification of primary LMNs as either melanocytoma or melanoma can be difficult. In some cases, obvious cytologic atypia is lacking, while microscopic CNS invasion and/or increased mitotic activity may be present (one to three mitoses per 10 HPFs and MIB‐1 LI ranging from 1% to 4%) 16. According to the WHO 2007 classification, such neoplasms can be diagnosed as intermediate‐grade melanocytic tumors 17. The clinical behavior of these intermediate‐grade melanocytic neoplasms is uncertain and needs further study 16, 17.

Differential diagnosis of circumscribed primary LMNs from other pigmented nervous system tumors

The main differential diagnosis includes metastatic melanoma to the CNS. These tumors are much more frequent as cutaneous melanoma has a higher incidence combined with a high propensity to metastasize to the CNS (CNS involvement in approximately 10% of cutaneous melanoma patients in clinical studies) 27, 136. This distinction is important as the prognosis of a patient with a primary LMN is substantially better than that of a metastatic melanoma to the CNS, which has a life expectancy of generally less than a year 19, 49, 110, 113. Primary leptomeningeal melanoma and metastatic lesions show histologic overlap, and histopathologic discrimination between primary or metastatic melanoma in individual patients is often impossible 16, 17. In addition, it is important to realize that primary cutaneous melanoma may show “spontaneous regression,” a prior excision of a cutaneous melanoma may not have been histologically examined or may have been misdiagnosed as a benign lesion, and primary melanomas may originate from less visible locations such as acral surfaces, nail beds, mucosal surfaces (genitals, sinonasal cavity, gastrointestinal tract) and the uveal tract. Therefore, before concluding that a CNS melanoma is a primary tumor, a thorough clinical examination as well as histologic revision of previously removed melanocytic tumors should be performed.

Clinically and radiologically, circumscribed primary LMNs can resemble meningeoma as both are leptomeningeal‐based tumors. Even histologically, the differential diagnosis may be challenging as both may demonstrate a nested growth pattern. Immunohistochemistry for EMA is helpful in this respect as melanocytomas are non‐reactive for Epithelial Membrane Antigen (EMA) 16.

Melanocytoma should also be differentiated from melanotic schwannoma, a rare variant of schwannoma composed of cells having the ultrastructure and immunophenotype of Schwann cells and demonstrating some melanocytic features in the form of intracytoplasmic melanosomes and being reactive for melanoma markers 6, 119. Melanotic schwannoma frequently occurs in association with cranial nerves and spinal nerve roots and the paraspinal sympathic chain, thereby showing overlap with primary LMNs. Discrimination is important because especially the psammomatous form of melanotic schwannoma is associated with the autosomal dominantly inherited Carney complex, a rare multiple neoplasia syndrome characterized by (cardiac) myxomas, multiple types of skin tumors and pigmented lesions, and endocrine tumors including pigmented nodular adrenocortical disease 21, 112, 115. Furthermore, a small percentage of melanotic schwannomas may show malignant behavior with distant metastases 119, 130. Immunohistochemistry is often of little help as both neoplasms are neural crest‐derived and generally positive for S100 and (other) melanocytic markers such as MelanA and HMB‐45. Reticulin stains and immunohistochemistry for basement membrane components can be helpful as there is generally pericellular staining in schwannomas compared with nested staining in melanocytoma, although the pericellular staining pattern is usually less pronounced in melanotic schwannomas 6, 60, 76.

Occasionally, other primary CNS tumors contain melanin pigment, for example melanotic medulloblastoma, melanotic neuro‐ectodermal tumor of infancy, pigmented glial/ependymal and choroid plexus tumors, and teratoma 124, 131. Further discussion of these extremely rare and non‐ or non‐pure melanocytic tumors is beyond the scope of this review.

Diffuse neoplasms

Melanocytosis

Melanocytosis is a diffuse proliferation of histologically benign appearing melanocytes in the leptomeninges, often with extension in the Virchow‐Robin spaces, but without frank invasion of the CNS parenchyma. Macroscopically, melanocytosis is visible as brown to black discoloration of the leptomeninges 17. Melanocytosis can remain asymptomatic, but once neurologic symptoms develop prognosis is generally poor, even in the absence of malignant transformation.

Melanocytosis most frequently occurs in children in the context of NCM. This rare, congenital neurocutaneous syndrome is characterized by the presence of large and/or multiple congenital melanocytic nevi (CMN) of the skin in association with primary melanotic lesions of the CNS. The latter include melanin depositions in the brain parenchyma (visible on T1‐weighted MRI) and/or a benign or malignant, primary LMN 65, 69. NCM shows no clear pattern of inheritance. Rarely, non‐melanocytic CNS neoplasms have been reported in association with CMN and NCM, including neurocristic hamartoma, choroid plexus papilloma and meningeoma 70.

Melanomatosis

Diffuse spread of malignant appearing primary melanocytic cells along the leptomeninges, often with superficial invasion of the brain parenchyma, is known as melanomatosis (Table 2) 17. This disease has a bimodal age distribution and may become manifest in children, with or without a context of NCM, as well as in adults, mostly in the fourth decade 3, 8, 105.

Melanomatosis is an extremely aggressive disease with high mortality. Especially in small biopsies, melanomatosis can histologically mimic metastasis of for example, cutaneous melanoma to the CNS. The absence of melanoma elsewhere in the body and its diffuse growth pattern on radiologic images (in contrast to localized lesions found in metastatic CNS melanoma) contribute to the diagnosis 124.

Molecular Characteristics of LMNs

Mutations in melanomas other than primary LMNs

Especially during the last decade molecular studies showed that melanoma is a heterogeneous disease with distinct oncogenic mutations in different subgroups of melanoma (Figure 2, Table 3) 31, 141. Activating mutations in the BRAF gene, encoding a member of the RAF family of serine/threonine kinases, are frequent in cutaneous melanoma, especially in those occurring in skin subject to intermittent sun exposure (present in approximately 50% of those tumors) 86. Activating BRAF mutations lead to constitutive activation of the mitogen‐activated protein kinase (MAPK) pathway, by transduction of signals from the cell surface to the nucleus through phosphorylation of a cascade of kinases that results in cell proliferation 41. Approximately, 75% of BRAF mutations involve the c.1799T>A [p.(Val600Glu)] alias BRAF^V600E hotspot mutation 24, 48.

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.

Table 3.

Frequency of oncogenic hotspot mutations in circumscribed LMNs in adults compared with melanoma of other body locations. Abbreviations: LMNs = leptomeningeal melanocytic neoplasms

	GNAQ codon 209	GNA11 codon 209	BRAF codon 600	NRAS codons 61, 12, and 13	HRAS codons 61, 12, and 13	KRAS codons 61, 12, and 13	KIT ex 11, 17
LMNs
Melanocytoma	6/12 (50%) 77	0/11 75	0/12 77	0/10 77	0/9 77	1/18 (6%)e 71	0/5 45
	3/6 (50%) 45	0/6 45	0/5 45	0/6 45	0/6 45		0/18 71
	0/5 96	1/5 (20% ) 96	1/18 (6%)a 71	0/18 71			0/8 139
	8/18 (44%) 71	6/18 (33%) 71	0/11 139	0/8 139
	41%	18%	2%a	0%	0%	6%e	0%
Intermediate‐grade melanocytic tumor	3/7 45	1/7 (14%) 45	0/3 77	0/1 77	0/1 77	Not reported yet	0/7 45
	0/3 77	1/5 (20%) 75	0/7 45	1/7 (14%) 45	0/7 45
	30%	17%	0%	13%	0%	Unknown	0%
Melanoma	1/3 (33%) 77	1/3 (33%) 45	0/3b 77	0/2c 77	0/3 77	Not reported yet	0/3 45
	0/3 45	1/4 (25%) 75	0/3 45	0/3c 45	0/3 45
	17%	29%	0%	0%	0%	Not reported yet	0%
Melanoma of other body locations
Uveal	45%–49% 102, 134	32% 134	<1% 29, 85, 148	<1% 29, 148	0% 125, 148	0% 140	10% 137
Skin	1% 22, 134	1% 134	∼50% 86	15%–20% 66, 81	2% 43	1%–2% 140	10% 30
Mucosal	<1%d 22, 68, 134	0% 134	∼10% 30, 31, 86	∼20% 13	<2% 64, 101	Rare 79	20% 30

This table includes all series reported up to now for LMNs in adults; case reports are not included in this table, but are discussed in the text.

^aKoelsche et al reported one BRAF^V600E mutation in their series of 18 melanocytomas. By unsupervised hierarchical cluster analysis of tumor methylomes the DNA methylation profile of this case clustered with the metastatic melanoma group instead of with melanocytomas, raising the question whether this case was truly a melanocytoma or rather a (metastatic) melanoma.

^bThe single BRAF^V600E mutation we previously detected in a leptomeningeal melanoma is not included here as we cannot rule out in retrospect that this was a metastasis from a skin melanoma; the patient underwent a skin excision with histology that could fit a regressed melanoma.

^cIn adult cases. Of note, NRAS mutations in LMNs in the pediatric setting are a frequent event; see text for further reading.

^dA single case of GNAQ mutation occuring in a mucosal melanoma has been reported 68.

^eUp to now, only one study looked for mutations in KRAS in primary LMNs. Koelsche et al found one KRAS mutation (c.179G>A) in 18 melanocytomas. The DNA methylation profile of this case, however, clustered with the melanotic schwannoma group instead of with melanocytomas.

Activating mutations in NRAS, one of the three major isoforms of the RAS family of GTPase proteins and an upstream signaling component in the MAPK pathway, are present in approximately 15%–20% of cutaneous melanomas and 20% of mucosal melanomas, but are very rare in uveal melanomas 13, 81, 148. NRAS mutations usually occur in codons 12, 13 or 61, and are mutually exclusive with BRAF^V600 mutations 37. Activating NRAS mutations cause aberrant signaling in several downstream cascades including the MAPK and the phosphatidylinositol 3‐kinase/protein kinase AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathways that are implicated in cell proliferation and survival 106. Cutaneous melanomas also frequently harbor mutations in the promoter region of the telomerase reverse transcriptase TERT (70%) 59.

In comparison with cutaneous melanoma, BRAF mutations are infrequent in mucosal melanomas (∼10%), in melanomas of the “non‐hair‐bearing skin” (acral melanomas, approximately 15%) and virtually absent in uveal melanomas 29, 86. Similarly, TERT promoter mutations are rare in these melanomas subtypes (eg, found in 0.5% of uveal melanomas) 35.

Instead, mucosal melanomas and acral melanomas relatively frequently harbor activating mutations and/or increased copy numbers of the gene encoding the receptor tyrosine kinase KIT (approximately 20%–40%) 30. Uveal melanomas and blue nevi frequently harbor activating, mutually exclusive GNAQ or GNA11 mutations. GNAQ mutations are found in about 45% of uveal melanomas and 83% of blue nevi, GNA11 mutations in about 32% of uveal melanomas and 6.5% of blue nevi. In both genes, the mutations most often involve codon 209 with only rarely mutations in codon 183 (1%–3%, in either gene) 102, 133, 134. Although so far a clear association between GNA11 or GNAQ mutational status and survival in uveal melanoma patients is lacking, the study of Van Raamsdonk et al suggested that GNA11^Q209 mutations occur especially in aggressive, metastatic tumors 12, 74, 134. Of note, oncogenic mutations in the GNAQ and GNA11 genes are extremely rare in cutaneous, mucosal and acral melanomas, as well as in common melanocytic, congenital and spitz nevi (Table 3) 22, 104, 107, 134.

Furthermore, inactivating mutations in the tumor suppressor BAP1 are frequent in metastatic uveal melanoma as well (approximately 80%) and are strongly associated with monosomy 3, which is a significant predictor for liver metastasis 52. Recently, hotspot mutations of the SF3B1 gene, encoding the splicing factor 3B subunit 1 and affecting RNA splicing, was found in 30% of uveal melanomas (especially in those tumors without monosomy 3) compared with only 1% of cutaneous melanomas 73, 88.

Adult patients with circumscribed primary LMNs

High frequency of GNAQ and GNA11 mutations

Only in 2009 resp. 2012, GNAQ and GNA11 mutations were reported for the first time to occur in LMNs 77, 96. Oncogenic mutations in these genes are found in benign as well as malignant LMNs and have up to now only been reported in adult patients with circumscribed tumors, except for a 15‐year‐old boy with a GNA11‐mutated melanocytoma in the series of Koelsche et al 28, 44, 45, 71, 75, 77, 96, 126. Like in uveal melanomas, activating mutations in GNAQ and GNA11 in LMNs mainly affect codon 209 and consist of substitution of glutamine to leucine [c.626 A>T (p.(Gln209Leu))] or, less frequently, by substitution to proline [c.626 A>C (p.(Gln209Pro))] 45, 71, 75, 77. Only a single case of spinal melanocytoma with a codon 183 GNAQ mutation {c.548 G>A [p.(Arg183Gln)]} has been described 96. A summary of mutation frequencies in LMNs is presented in Table 3. Based on published series so far, GNAQ mutations are present in about 39% of melanocytomas and 17% of primary leptomeningeal melanomas, while GNA11 mutations are present in approximately 17% of melanocytomas (including intermediate‐grade melanocytic neoplasms) and 29% of primary leptomeningeal melanomas. Up till now, the prognostic significance of GNAQ and GNA11 mutations in primary LMNs is unclear, nor is there a clear association with other clinicopathologic characteristics.

Other molecular findings

In the few larger series on primary LMNs reported up to now, BRAF^V600E mutations are very rare. (Table 3) Of note, the number of esp. primary leptomeningeal melanoma cases analyzed is limited 45, 71, 77, 139. A BRAF^V600E mutation has recently been reported in an unusual case of leptomeningeal melanocytoma in assocation with a congenital nevus of Ota in a 15‐year‐old boy. This melanocytoma did not harbor any GNAQ^Q209 mutations, however, codon 183 and GNA11 mutation status was not investigated 95. Koelsche et al found a single case with a BRAF^V600E mutation in their series of 18 melanocytomas. By unsupervised hierarchical cluster analysis of tumor methylomes, however, the DNA methylation profile of this case clustered with the metastatic melanoma group instead of with the melanocytoma group 71. This latter finding may be explained as proof of an unusual BRAF‐mutational profile in a primary leptomeningeal tumor as well as a reason to consider this lesion rather as metastatic melanoma. Based on current literature, the BRAF^V600E mutation seems to be very rare in primary LMNs, but more cases need to be analyzed.

Most studies have reported absence of NRAS mutations in primary LMNs in adult. A single NRAS^Q61K‐mutated intermediate‐grade melanocytoma was found in a series of 15 primary LMN cases in adult patients. This concerned a tumor in the spinal region in a 40‐year‐old woman. Whether this patient had a congenital background of her disease is unknown 45. Importantly, in primary LMNs in children NRAS mutations occur more frequently (see later). In a few studies, HRAS, KRAS and KIT mutations were examined in primary LMNs and reported to be absent (Table 3). Only the study of Koelsche et al reported a KRAS mutation in a melanocytoma (c.179G>A, 1/18) although the DNA methylation profile of this case clustered with the melanotic schwannoma group rather than with the melanocytomas 71.

Similar to uveal melanoma, TERT promoter mutations are reported to be absent in primary LMNs 46. It remains to be determined whether inactivating mutations in BAP1 frequently present in uveal melanoma also characterize primary LMNs.

In a recent study, we demonstrated monosomy 3 in a GNAQ‐mutated leptomeningeal melanoma. This patient showed distant metastases in bone and lungs, but no liver metastases. A gain of chromosome 6p was found in a GNA11‐mutated leptomeningeal melanoma without distant metastases, while gain of whole chromosome 6 was present in an intermediate‐grade melanocytic tumor showing local recurrence 75. Koelsche et al also demonstrated that gain of chromomosome 6 or 6p is frequently present in melanocytomas (8 out of 18 cases) in addition to loss of chromosome 3 or 3q (4/18) 71. These results suggest that primary LMNs share not only mutations, but also copy number variations (CNVs) with uveal melanoma. It is presently unclear whether these CNVs have prognostic value in LMNs as well.

GNAQ and GNA11 mutations: diagnostic potential

Acknowledging the relatively high incidence of cutaneous melanoma and its frequent spread to the CNS vs. the low incidence of primary LMNs, it is much more likely that a melanoma in the CNS represents a metastatic lesion than a primary LMN. Still, discriminating these entities is relevant because of different patient work‐up and the substantially better prognosis for patients with a primary LMN 49, 113, 123.

GNAQ and GNA11 mutational analysis can be useful in this differential diagnosis as presence of a GNAQ or GNA11 mutation in a CNS melanocytic tumor strongly favors a primary leptomeningeal origin over metastasis of cutaneous melanoma. (Figure 3) Theoretically, in case of a GNAQ or GNA11 mutation, metastasis of uveal melanoma or malignant blue nevus to the CNS should be considered in the differential diagnosis. An example illustrating the diagnostic potential of this analysis is given in Figure 4. Conversely, knowing that about 50% of cutaneous melanomas carry a BRAF^V600 mutation and that this mutation is very rare in primary LMNs, demonstration of this BRAF mutation in a CNS melanocytic tumor strongly favors metastatic cutaneous melanoma over primary LMN 45, 71, 75, 139.

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 

GNAQ and GNA11 mutational analysis can have some value in the differential diagnosis of primary LMN vs. melanotic schwannoma 76. Correct diagnosis of (psammomatous) melanotic schwannoma is important to select patients who need further clinical work‐up for Carney complex, a potentially life‐threatening disease especially because of the frequent occurrence of cardiac myxomas 115, 120. Inactivating mutations in the regulatory subunit type 1 alpha gene of protein kinase A (PKA) (PRKAR1A, at chromosome region 17q22–24) are present in up to 70% of patients with Carney complex 58, 115. Mutations in PRKAR1A mostly result in PRKAR1A haploinsufficienty with loss of PRKAR1A expression and inactivation of the regulatory subunit type 1 alpha resulting in increased PKA activity 118 Instead of hotspot mutations, PRKAR1A mutations are spread over ten exons with approximately 120 pathogenic sequence variants described 15, 58. PRKAR1A mutational analysis is therefore not practical for routine testing when a melanotic schwannoma is considered. We previously showed that GNAQ^Q209 mutations were absent in a series of nine melanotic schwannomas 76 and subsequently found that GNAQ^R183 and GNA11^Q209/R183 mutations were absent in these tumors as well (unpub. data). Koelsche et al identified in their series of 14 melanotic schwannomas one case with a GNAQ^Q209L mutation and another one with a GNA11^Q209P mutation. The DNA methylation profiles of both cases, however, clustered with the melanocytomas and not with the melanotic schwannomas, suggesting that these cases might have been melanocytomas 71. The data at present thus suggest that GNAQ and GNA11 mutation analysis are helpful in the differential diagnosis of primary LMN vs. melanotic schwannoma although more cases of especially these latter tumors need to be tested.

Investigation of the mutational status of the BRAF, NRAS, GNAQ and GNA11 genes can easily be performed by Sanger sequencing or next generation sequencing (NGS) technologies 38. The relevant mutations in these genes are hotspot mutations, allowing targeted sequencing of the predefined regions of the respective genes. The major advantage of NGS is the lower amount of DNA that is needed for the analysis and the higher sensitivity compared with Sanger sequencing (detection of 2%–10% vs. 15%–25% allele frequency). For sequencing technologies, the DNA specimens are extracted via standard procedures, although the quality of the sequencing result from highly pigmented lesions may improve by an additional purification step.

GNAQ and GNA11 mutations: pathobiologic aspects

The preferential occurrence of GNAQ and GNA11 mutations in primary LMNs, uveal melanomas and blue nevi suggests a common pathogenetic mechanism. These tumors originate from melanocytes that are not epithelium related (blue nevi are thought to be derived from a small pool of melanocytes located in the dermis that have not reached the epidermis during embryogenesis 82 ). In contrast, common melanocytic nevi and cutaneous melanomas are derived from intra‐epidermally located melanocytes 92. Apparently, epidermal and non‐epidermal melanocytic cells are vulnerable to different oncogenic mutations. Interestingly, in mice indeed differences in epidermal vs. non‐epidermal melanocytes were found regarding their requirement of growth and differentiation signals 7.

GNAQ and its paralogue GNA11 map on chromosomes 9q21.2 and 19p13.3, respectively 61. They encode the α subunit of G‐proteins, which couple G‐protein coupled receptors (GPCRs) to various intracellular pathways 62. G‐proteins are heterotrimeric GTP‐binding proteins and consist of α and βγ subunits 62. The α subunit genes are grouped into four classes; Gα_s, Gα_i/o, Gα_q/11 and Gα_12/13; GNAQ and GNA11 belong to the G_q/11 class of α subunit genes 61, 99, 142. G‐proteins function as a molecular switch: activation of the GPCR catalyzes the exchange of guanosine diphosphate (GDP), bound to the inactive α subunit, for guanosine triphosphate (GTP), resulting in dissociation of the complex 62. The Gα subunit then activates diverse effector proteins, depending on the Gα subunit type, by the release of second messengers. GTP hydrolysis and re‐association of the complex into its inactive, GDP‐bound state is largely regulated by the intrinsic GTPase activity of the α subunit 62.

The glutamine at codon 209 or arginine at codon 183 of GNAQ and GNA11 is essential for GTP hydrolysis and mutations at these codons cause impaired GTPase activity. This leads to constitutive activation of downstream intracellular pathways including the MAPK pathway via activation of protein kinase C (PKC) by β‐phospholipase C 53, 61, 87, 114, 133. Another pathway regulated by GPCRs is the Hippo‐YAP signaling pathway 147. Recently, it was demonstrated that this pathway is implicated in GNAQ/GNA11‐mutated uveal melanoma, that the transcription co‐activator YAP can be specifically activated by GNAQ/GNA11 mutations (Q209), and that YAP is important for GNAQ‐induced neoplastic transformation (Figure 2) 42, 146.

GNAQ/GNA11 mutations: therapeutic potential

Patients with metastatic cutaneous melanoma carrying the BRAF^V600 mutation can nowadays be treated with selective BRAF inhibitors (eg, vemurafenib and dabrafenib), sometimes with impressive (albeit temporary) clinical and radiologic response 24, 36, 48. Treatment with the MEK inhibitor trametinib is approved by the Food and Drugs Administration as monotherapy for unresectable or metastatic BRAF^V600‐mutated melanoma in the USA while the MEK inhibitor MEK162 has shown efficacy in NRAS‐mutated advanced melanoma in a phase 2 study 9, 143. Similarly, treatment with KIT inhibitors such as imatinib and sorafenib has shown objective responses in advanced KIT‐mutated cutaneous melanomas 50, 56.

At present, there are neither GNAQ‐ nor GNA11‐mutated cell lines from primary human LMNs available and preclinical and clinical evidence for therapeutic efficacy of targeted treatment in patients with primary LMNs is lacking. Still, inhibition of GNAQ/GNA11‐dependent signaling pathways may as well be of interest for targeting LMNs carrying these mutations.

To date, there are no direct inhibitors of mutant‐GNAQ (or GNA11) and current focus is on inhibition of components of downstream‐activated pathways. One of these downstream pathways is the MAPK pathway that is activated by PKC through the release of diacylglycerol by β‐phospholipase C (Figure 2) 53, 61, 114, 133. The PKC inhibitor enzastaurin was shown to have antitumor activity against GNAQ‐mutated uveal melanoma cell lines via inhibition of the PKC/ERK 1/2 pathway 144, 145 Very recently, a phase 1 trial with the PKC inhibitor AEB071 completed dose escalation in GNAQ/GNA11 mutant uveal melanoma patients 122. Combination of PKC inhibition and MEK inhibition was demonstrated to be synergistic in suppressing MAPK signaling in GNAQ‐mutated uveal melanoma cell lines and combination trials are ongoing 25, 122. Also, GNAQ‐mutated uveal melanoma cell lines were shown to be sensitive to inhibition of MEK, resulting in decreased levels of pERK and decreased proliferation 5, 40, 91, 133. Recently, a phase II trial showed that the MEK inhibitor selumetinib (AZD6244) resulted in a modestly improved progression‐free survival compared with chemotherapy in metastatic uveal melanoma patients with GNAQ or GNA11 mutation 23.

Using a siRNA strategy, knockdown of GNAQ was demonstrated to inhibit the PI3K/AKT/mTOR pathway as well 4. Dual pathway inhibition with a combination of MEK inhibitor and PI3K inhibitor or mTOR kinase inhibitor was described to be synergistic in inducing apoptosis and reducing cell viability in GNAQ mutant uveal melanoma cell lines, respectively 4, 55, 67. A combination phase 2 trial of the MEK inhibitor trametinib or trametinib plus the AKT inhibitor GSK2141795 is currently randomizing patients 122. Also, as the YAP inhibitor verteporfin was shown to selectively inhibit growth of GNAQ/GNA11 mutant uveal melanoma cell lines, this might be a promising therapeutic strategy for patients with primary LMNs as well 42, 146.

Children with primary LMNs

NRAS mutations in pediatric LMNs and NCM

Post‐zygotic, somatic mutations in NRAS were recently shown to underlie the pathogenesis of NCM in most of the cases. These mutations mainly affect codon 61 of NRAS and have been detected in diffuse as well as circumscribed LMNs in children 45, 70, 78, 103, 117. In a very recent series, 12 of 16 patients with NCM harbored a somatic NRAS^Q61 mutation in their CMN (75%) 117. Moreover, several studies on NCM have demonstrated an identical, somatic NRAS^Q61 mutation in multiple of the CMN as well as in the LMN in the same patients 70, 78, 103. Table 4. This phenomenon can be explained by assuming that early during embryogenesis a melanocyte precursor cell acquires a somatic NRAS mutation, which gives rise to a mosaic pattern of NRAS‐mutated cells that further migrate and colonize the skin and/or leptomeninges. This pathogenetic mechanism fits the spectrum of mosaic RASopathies that is characterized by post‐zygotic mutations resulting in the presence of two genetically distinct cell populations in the same organism 51. The exact timing of acquisition of the NRAS mutation during embryogenesis (and thus the position of the migrating precursor cell at that time) might influence the eventual phenotype (Figure 5).

Table 4.

Overview of NRAS mutations detected up to now in both CNS lesions as well as in CMN of patients with NCM. Abbreviations: CMN = congenital melanocytic nevus; CNS = central nervous system; NCM = neurocutaneous melanosis

Age (years)	CNS melanocytic/melanotic lesion	Location	NRAS mutation in the CNS tumor	Identical NRAS mutation in the patient's CMN	Reference
7	Circumscribed melanoma	Right frontotemporal	Q61K	Yes	Pedersen et al 103
8	Melanocytosis	Not otherwise specified	Q61R	Yes, in multiple CMN	Kinsler et al 70
10	Primary melanomaa	Cerebellum	Q61R	Yes, in multiple CMN	Kinsler et al 70
13	Melanocytosis	Spinal	Q61K	Yes	Küsters‐Vandevelde et al 78
2 months	Melanin deposition on T1‐weighted MRI	Right cerebellopontine cisternb	G13Rc	Yes	Shih et al 121

^aIn a background of diffuse leptomeningeal melanocytosis.

^bAt the age of 21 months, this patient also presented with a myxoid, non‐melanocytic mesenchymal tumor in the left occipital region; this tumor harbored an NRAS^G13R mutation.

^cWhich was also present in the patient's CMN.

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.

There is some evidence suggesting that post‐zygotic NRAS mutations in NCM (and CMN) might occur before specification of neural crest cells to the melanocytic lineage, and thus possibly leading to neuroectodermal‐derived tumors other than melanocytic tumors in these patients. Kinsler et al for instance detected a somatic NRAS^Q61R mutation in a non‐melanocytic CNS tumor, that is, a spinal neurocristic hamartoma, occuring in an 8‐year‐old child with NCM and leptomeningeal melanocytosis 70. In addition, they detected a somatic NRAS^Q61R mutation in a meningeoma and choroid plexus papilloma in two patients with large CMN. Very recently, Shih et al demonstrated an NRAS^G13R mutation in a CNS mesenchymal (but non‐melanocytic) tumor occurring in a young child with NCM 121. These NRAS mutations were also present in the CMN of these patients suggesting that they occurred very early during embryogenesis in multi‐ or oligopotent precursor cells. Of note, the NRAS^G13R mutation in the NCM patient in the study of Shih et al is the first report of an NRAS mutation other than NRAS^Q61 in NCM, although it is uncertain whether this NRAS^G13R mutation was truly a post‐zygotic mutation as it was also present in normal tissue albeit in lower allelic frequency. This patient in addition had a germline, single‐nucleotide polymorphism in the MET gene that encodes the receptor for hepatocyte growth factor/scatter factor (HGF/SF). In a transgenic mouse model, inappropriate expression of HGF/SF has been shown to result in a phenotype similar to NCM 128.

We recently presented an NRAS‐driven mouse model of NCM and primary leptomeningeal melanoma using the Cre‐LoxP technology 103. In this model, the embryonic expression of oncogenic NRAS^G12D in melanocytes of developing mice embryos induced congenital melanocytic lesions of the skin, congenital melanocytosis of the leptomeninges and early onset primary leptomeningeal melanoma. However, NRAS mutations are in itself insufficient for melanoma development, as is illustrated by their occurrence in benign CMN 11. Identifying the events that synergize with oncogenic NRAS is needed in order to better understand the pathogenesis of NRAS‐mutated leptomeningeal melanoma. A possible contributing event could be deletion of CDKN2A (encoding p16^INK4A), as deletion of CDKN2A has been shown to cooperate with NRAS^Q61K to induce melanoma in mouse models earlier 1, 26 and was detected in a primary NRAS‐mutated melanoma arising in the cerebellum of a 10‐year‐old child 70.

Other molecular findings

A very recent study of Saldago et al reported a BRAF^V600E mutation in the CMN of two NCM patients (2/16, 12.5%) 117. Although the LMNs of these two patients were not investigated, these results suggest that BRAF mutations might play a role in some NCM patients. Also, a minority of patients with large or giant CMN outside the context of NCM harbors BRAF^V600E instead of NRAS^Q61 mutations 33. Additional studies including testing of CNS lesions will have to confirm a role for BRAF mutations in some NCM patients, as this could have consequences for targeted therapy.

Currently, knowledge on CNVs in LMNs in children is largely lacking. In the single study that has been published on this subject, Kinsler et al reported absence of large gains or losses in one case of NRAS‐mutated melanocytosis in an 8‐year‐old boy with NCM (using array CGH) 70. In contrast, they detected multiple gains and losses in a primary NRAS‐mutated melanoma in the cerebellum of a 10‐year‐old child with NCM that developed liver metastases. The aberrations in this melanoma included, among others, loss of whole chromosome 3, gain of chromosome 8 and loss of 9p24.3–p21.1, the latter including the CDKN2A locus 70. However, given the small number of cases studied, the diagnostic and prognostic significance of these CNVs is unclear.

NRAS mutations: therapeutic potential

In contrast to mutant BRAF, small molecules that selectively inhibit mutant NRAS are presently not available 106. One of the strategies for NRAS‐mutated neoplasms is the use of inhibitors that target downstream‐activated cascades such as the MAPK pathway and the PI3K/AKT/mTOR pathway (Figure 3) 66. Melanoma cell lines harboring NRAS mutations were shown to be sensitive to inhibition of MEK 40. A recent phase 2 trial with MEK162, a potent MEK inhibitor, has revealed efficacy in some patients with NRAS mutant melanoma, including two patients with NRAS‐mutated brain melanoma metastases 9. As NRAS activates multiple downstream pathways, there is evidence that combination of inhibitors of proteins downstream of NRAS such as MEK, ERK and PI3K/mTOR effectors will be more effective, and clinical trials with such combinatorial approaches are currently underway 66, 109, 111.

We previously demonstrated that melanoma cells derived from primary NRAS^G12D‐mutated brain melanomas of mice are sensitive to MEK inhibitors in vitro, and that the MEK inhibitor PD184352 delayed tumor growth in in vivo allograft experiments using NRAS^G12D‐mutant cells from a primary mouse brain melanoma 103. The YP‐MEL cell line is one of the few human NCM cell lines available for study. This cell line harbors an NRAS^Q61K mutation and was recently shown to be sensitive to several MEK inhibitors and inhibitors of mTOR and PI3K in vitro 98, 116. Whether MEK inhibitors can effectively target NRAS‐mutated LMNs is to be further investigated, but some effect on pERK protein level and MIB‐1 LI was demonstrated in a patient with NRAS‐mutated leptomeningeal melanocytosis experimentally treated with MEK162 78.

Conclusions

Primary LMNs represent a spectrum of rare neoplasms occurring in adults as well as in children. Distinct clinicopathologic and genetic features characterize these tumors. Oncogenic mutations in hotspots of the GNAQ and GNA11 genes are frequent in circumscribed primary LMNs in adults, while in children, oncogenic mutations in NRAS are frequent both in circumscribed and diffused LMNs. The presence of mutations in GNAQ and GNA11 in LMNs suggests a pathogenetic mechanism similar to uveal melanoma and blue nevi and supports the idea of distinct subtypes of melanocytes that are preferentially targeted by distinct oncogenic mutations. In the congenital setting, acquisition of somatic mutations in NRAS early during embryonic development underlies the pathogenesis of NCM. Of note, the distinction between adult and pediatric setting is somewhat arbitrary, as adult patients may have a congenital background of their disease, but were only diagnosed later in life while not all LMNs that occur in children are necessarily truly congenital in origin.

The frequent presence of GNAQ/GNA11 mutations in primary LMNs is helpful in the differential diagnosis with metastasis of especially cutaneous melanoma to the CNS. Adequate diagnosis of primary vs. metastatic melanoma in/around the CNS has prognostic relevance, the patients with melanoma metastatic to the CNS having a grimmer prognosis. As for other CNS tumors, smart integration of histologic and molecular information can be expected to result in a more robust and clinically relevant classification of primary LMNs 83. Also, further elucidation of the molecular aberrations underlying primary LMNs may well provide novel therapeutic options for these patients.