Central Nervous System Melanomatosis Arising In Braf V600e Mutated Neurocutaneous Melanosis: A Case Report

Figure 2: Histological features of skin (A-D) and central nervous lesions (E-F). Skin biopsy revealed a compound congenital nevus, comprising a junctional component with mild dysplasia (A, hematoxylin-eosin 20x), partial fusion of nests (A), and focal pagetoid spread (B, hematoxylin-eosin, 10x), and a dermal component with preserved maturation, extending around cutaneous adnexa and to the hypodermis (C-D, hematoxylin-eosin, 10x). CNS proliferation (E, hematoxylin-eosin, 10x – F, hematoxylin-eosin 20x) was composed of cuboidal and ovalar melanocytes involving meningeal tissues and focally invading brain parenchyma, without mitoses, hemorrhage, or necrosis, consistent with melanomatosis.

The diagnostic work-up included a CMN ultrasound, which highlighted the presence of solid hyperechoic nodular lesions, the largest two located on the lower back and on the left gluteus. Due to slow but progressive enlargement, the lesion on the back was biopsied.

Histological examination (figure 2A-D) revealed a compound congenital nevus, comprising a junctional component with mild dysplasia, partial fusion of nests and focal pagetoid spread, and a dermal component with preserved maturation, extending around cutaneous adnexa and to the hypodermis. A single mitosis/mm² was observed. The melanocytic proliferation showed positivity for S100, SOX10, and HMB45 (limited to the junctional component), negativity for ALK, focal PRAME positivity ³³ and retained BAP1 expression. The proliferative index, evaluated with MIB1-Ki67 antibody, was esteemed to be around 5%.

A fluorescence in situ hybridization (FISH) analysis to assess P16 (9p21) gene status³⁴, performed separately on junctional and dermal components, revealed the absence of homozygous deletion, arguing against a melanoma diagnosis along morphological and architectural features. Hence, a diagnosis of a compound congenital nevus with junctional dysplasia and focal pagetoid spread was made; such features can be commonly encountered in the setting of giant congenital nevi, prompting however a careful follow-up of the patient.

A few weeks later, the patient underwent a second CNS MRI, performed 4 months from birth, which highlighted an increase in the number and size of both intra-axial and meningeal lesions, with involvement of the left cerebellar hemisphere and the onset of a left parietal cortical-subcortical lesion, suggestive for extensive CNS melanocytosis (figure 1 B-C). To better frame the neurological involvement, an excisional biopsy of a left parietal cortical-subcortical lesion was subsequently performed. Histology (figure 2E-F) revealed a proliferation composed by cuboidal and ovalar melanocytes involving meningeal tissues and focally invading brain parenchyma, without mitoses, hemorrhage or necrosis. The lesion, due to its invasiveness, was thus interpreted as CNS melanomatosis.

As previously stated, and according to the latest update of the WHO skin tumor classification³⁵, CNS melanomatosis is defined as a malignant proliferation of melanoma cells arising from leptomeningeal melanocytes, exhibiting necrosis, atypia, mitotic activity and/or brain parenchyma invasion. Brain parenchyma invasion alone, even in the absence of the above-mentioned histological features, warrants a melanomatosis diagnosis. Melanomatosis is almost exclusively associated with NCM, and its prognosis is abysmal, with rapid disease progression due to brain parenchyma invasion. Moreover, melanomatosis, as well as melanocytosis, involves widely the subarachnoidal spaces, but it can also present with focal or multifocal nodularities, as it is in our case³⁶. Such “nodular” presentation must not induce one to the incorrect diagnosis of what the current WHO classification defines as “circumscribed” or isolated melanocytic proliferations, such as CNS melanocytoma or melanoma, which are not associated with NCM¹⁵.

In fact, our case CNS lesion, due to its nodular contour and histological features, could have been at first interpreted as CNS melanocytoma, and specifically a “melanocytic neoplasm of intermediate grade”. This term was originally introduced by Brat et al.³⁷ to identify cases with intermediate behavior between CNS well-differentiated melanocytoma and CNS melanoma, both presenting as focal lesions; specifically, melanocytic neoplasms of intermediate grade showed sheet-like growth pattern, microscopic CNS invasion and/or occasional mitoses (>1.5 mitoses/mm²). This category is now included in the current WHO classification as melanocytoma of intermediate grade¹⁵. Despite the usual presentation as isolated lesions, few cases of intermediate-grade melanocytoma have been reported in association with nevus of Ota and in one case with NCM^38–40. However, we personally believe that such cases could be reclassified within the melanocytosis or melanomatosis spectrum, according to current classification^15,41.

For a better understanding of the case, we performed a multiparametric molecular analysis of both skin and CNS lesions by means of Next Generation Sequencing (NGS) with a “hot-spot cancer panel” through Personal Genome Machine-IonTorrent technology. In both tissues we highlighted the presence of p.(Val600Glu) variant in BRAF exon 15, observed in 25% of DNA extracted from skin (50% cellularity) and in a small amount (1%) of DNA extracted from CNS lesion (30% cellularity).

Clinically, the patient is surprisingly asymptomatic at two years from diagnosis, with no signs of neurological involvement and no variation in CNS lesions at MRI. He is monitored periodically, with no apparent need for specific therapeutic approaches.

In conclusion, we believe our case stands out for two interesting reasons. First, it represents a rare case of melanomatosis with diffuse and multifocal nodular presentation arising in the context of NCM; such presentation stresses the importance of considering NCM as a syndrome in which a spectrum of melanocytic lesions can be observed, sometimes with misleading clinical and histological features that hamper a clear-cut diagnosis based on current classification. Secondly, our case belongs to the small number of BRAF mutated NCMs presenting with an increased number of proliferative nodules, in accordance with what was previously reported by Salgado et al.²⁹. In contrast with previous studies^30,42, Salgado et al. did not observe a significant better clinical course for BRAF mutated lesions. Despite the short follow-up and the neuropathological picture, our case did not show any neurological symptoms and presented with an indolent clinical course.

In conclusion, our case contributes to the description of the rare subgroup of BRAF-mutated NCM, where the application of targeted therapies might hold a promising role.