Final Diagnosis -- Leptomeningeal Melanocytosis


Leptomeningeal melanocytosis in the context of neurocutaneous melanosis (NCM), harboring an NRAS mutation (Q61K).


NCM is a rare congenital phakomatosis characterized by primary melanocytic tumors of the CNS associated with large or multiple congenital cutaneous nevi and malformative lesions of the posterior fossa such as Dandy-Walker malformation (1). The neurological tumor accompanying this entity can be diffuse when there is a widespread involvement of the meninges (melanocytosis or melanomatosis) or circumscribed (melanocytoma, melanoma) and benign/low grade (melanocytosis and melanocytoma) or malignant (melanomatosis and melanoma). Metastatic melanocytic tumors outnumber primary melanocytic neoplasms and therefore the diagnosis of a primary CNS melanocytic lesion is challenging. Pathological evaluation of small neurosurgical samples can be difficult since atypia and mitoses define grading into low, intermediate and high grade lesions (4). Intracranial hypertension symptoms are often related to involvement of Virchow-Robin perivascular spaces by melanin or melanocytes, which is not a sign of direct invasion.

The treatment of CNS melanocytosis is not well established and the prognosis is variable but often poor. Unlike melanocytoma, complete surgical excision cannot be achieved due to diffuse dissemination. The role of chemotherapy or radiotherapy is not clear in this disease which is pathologically benign but often lethal. Symptomatic treatment, like in our case with ventriculoperitoneal shunt, is therefore often applied. Recently, Ruan et al. (3) described a targetable mutation in pediatric NCM using an experimental model. Their study revealed NRAS Q61K mutation raising the possibility of MEK inhibition. Nevertheless these results need to be evaluated in a multicentric prospective study. Primary CNS melanocytic tumors of the childhood, either melanoma or melanocytosis, have recently been show to harbor NRAS mutations. Our case is consistent with these previously published findings, highlighting the importance of the NRAS gene in the development of the disease. There is thus a potential therapeutic application with MEK (MEK-162) inhibitors. A patient with leptomeningeal melanocytosis in the context of NCM was treated with a MEK-inhibitor, but died five days later, without thus establishing clinical response. However, when comparing pre- and post-treatment samples the authors found lower MIB-1 expression and lower pERK expression, suggesting a potential effect of MEK inhibiting therapy. Our case seemed to represent the less aggressiveness of NCM with NRAS mutation, since one year later, the patient is still alive. On the contrary, Salgado CM et al. showed that amplification of mutated NRAS seems to represent a new genetic mechanism leading to melanoma in the context of NCM. In the absence of adequate conventional therapies for this rare tumor (2), our case illustrates the possible interest of mutational profiling for "druggable" gene mutations, like anti-MEK therapy. Physicians should consider this rare entity when there are findings of congenital nevi, posterior fossa abnormality and a melanocytic tumor of the CNS. A careful cutaneous examination is also required when a melanocytic CNS lesion is found.


  1. Koelsche C, Hovestadt V, Jones DTW, Capper D, Sturm D, Sahm F, et al. Melanotic Tumors of the Nervous System are Characterized by Distinct Mutational, Chromosomal and Epigenomic Profiles. Brain Pathol. 2015; 25: 202-8.
  2. Küsters Vandevelde HVN, Küsters B, van Engen-van Grunsven ACH, Groenen PJTA, Wesseling P and Blokx. Primary Melanocytic Tumors of the Central Nervous System: a Review with Focus on Molecular Aspects. Brain Pathol. 2015; 25:209-26.
  3. Ruan Y, Kovalchuk A, Jayanthan A, et al. Druggable targets in pediatric neurocutaneous melanocytosis: Molecular and drug sensitivity studies in xenograft and ex vivo tumor cell culture to identify agents for therapy. Neuro Oncol. 2015; 17:822-31.
  4. Salgado CM, Basu D, Nikiforova M, Hamilton RL, Gehris R, Jakacki R, Panigrahy A, Yatsenko S, Reyes-Múgica M. Amplification of mutated NRAS leading to congenital melanoma in neurocutaneous melanocytosis. Melanoma Res. 2015; 25:453-60.

Contributed by Cyril Habougit, MD; Fabien Forest, MD; Claire Boutet, MD, PhD; Catherine Douchet, MD; Jean-Louis Stephan, MD, PhD; Marie-Laure Stachowicz; Francois Vassal, MD; Michel Péoc'h

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