Central Nervous System Melanomatosis Arising In Braf V600e Mutated Neurocutaneous Melanosis: A Case Report by Barbara Valeri by Journal of Clinical Case Reports, Medical Images and Health Sciences

Central Nervous System Melanomatosis Arising In Braf V600e Mutated Neurocutaneous Melanosis: A Case Report by Barbara Valeri in Journal of Clinical Case Reports, Medical Images and Health Sciences

Abstract:

Neurocutaneous melanosis (NCM) is a rare congenital syndrome defined by the combination of large or giant congenital melanocytic nevi and leptomeningeal melanocytic proliferation. NCM harbors per se an increased risk, as high as 12%, of malignant transformation to melanoma, arising in the context of either the congenital nevi or the central nervous system. The vast majority (75%) of NCM is a result of somatic mosaicism due to a single postzygotic mutation involving NRAS codon 61, which can be found both in skin and central nervous system localizations. BRAF V600E mutation is present only in a minority of patients with NCM (~12.5%). Here we report the rare case of a BRAF V600E mutated NCM complicated by central nervous system melanomatosis, defined as a diffuse or multifocal meningeal proliferation of melanoma cells derived from leptomeningeal melanocytes and exhibiting CNS invasion. Despite the usual abysmal prognosis of such condition, our case was characterized by an indolent course, and, to date, it did not need aggressive therapies. 

Introduction:

Neurocutaneous melanosis (NCM), first reported by Rokitansky in 18611, is a rare congenital syndrome characterized by large or giant congenital melanocytic nevi (CMN) in association with meningeal or brain parenchyma melanocytic proliferation². CMN are melanocytic in utero proliferations harboring an increased risk (as high as 12% in large lesions) of melanoma transformation during infancy or adulthood3–6. CMNs can be distinguished as small, medium, large, and giant, according to their greatest diameter's projected adult size (PAS). Large CMNs (LCMN) measure ≥ 20 cm, while giant CMNs (GCMN) exceed 40–50 cm7,8. The relationship between CMNs and NCM is yet to be fully understood; approximately 2 to 12% of individuals with LCMN will develop NCM. LCMN extension, facial or dorsal axial distribution, and the presence of satellite nevi are linked to a higher risk of NCM. Nonetheless, NCM is a rare syndrome, with approximately 300 cases reported worldwide 9,10. NCM does not show any sex predilection and occurs more often among Caucasians, with few sporadic cases in black patients11,12. NCM skin lesions encompass CMN, benign proliferative nodules within CMN, and malignant transformation of CMN or proliferative nodules13,14. Central nervous system 

(CNS) melanocytic proliferations arise from leptomeningeal melanocytes and can occur in the shape of melanocytosis, defined as a benign diffuse of multifocal meningeal proliferation of bland melanocytes, or melanomatosis, defined as a malignant diffuse or multifocal proliferation of melanoma cells exhibiting atypia, necrosis, mitotic activity and/or brain parenchyma infiltration. Brain parenchyma infiltration per se, even in the absence of marked cytological abnormalities and mitotic activity, should prompt a melanomatosis diagnosis15. NCM patients may be symptomatic, presenting with signs and symptoms of intracranial hypertension and/or a variety of neurological disturbs (ranging from seizures to cranial nerve palsies to eventual neurological deterioration), all due to CNS melanocytic proliferation16. Diagnosis of NCM is based on clinical observation and MRI findings, represented by a subtle increase in T1-weighted sequences and a decrease in T2-weighted sequences, with or without evidence of plaques or nodular lesions4,10,17–21. Most patients are neurologically asymptomatic; in these patients, symptoms onset generally marks the beginning of an aggressive clinical course, with poor prognosis even in the absence of malignant transformation and death occurring within 2–3 years of diagnosis22–24. 

to a single postzygotic mutation involving NRAS codon 61, which can be found both in skin and central nervous system localizations25. BRAF V600E mutation, which is mostly found in non-congenital nevi26,27, is present only in a minority of patients with NCM (~12.5%) and has been documented in approximately 30% of small-medium CMNs, where it is likely to be associated with a better outcome and more benign clinical course28–30. NCM requires prompt diagnosis and accurate surveillance, including essentially physical examination and brain/spinal cord magnetic resonance imaging (MRI)13. NCM treatment, due to the small number of cases, still poses challenging problems. The main strategies for skin lesions are represented by surgical removal, while options for CNS lesions are neurosurgical shunt placement, surgery, and/or chemotherapy13,22,23. In addition, biologically targeted therapies hold a promising role in NCM therapy, such as drugs targeting the MEK pathway, PI3K/mTOR pathway, and the RAS-ERK pathway 13,31,32 We report a peculiar case of NCM with CNS melanomatosis, harboring a BRAF V600E mutation both in skin and CNS lesions

Case Presentation and Discussion:

nevus with hypertrichosis, involving the genital area and buttocks, was referred to our Dermatology Unit due to the appearance of at least five proliferative nodules within the GCMN, located on the lower back and left gluteus and measuring between 2 and 5 cm in greatest diameter (figure 1 A). The patient had no neurological signs or symptoms, although a CNS MRI performed shortly after birth had shown intra-axial and meningeal localization diagnostic with melanocytosis and consistent with NCM. 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 positivity33 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 intermediategrade melanocytoma have been reported in association with nevus of Ota and in one case with NCM38–40. However, we personally believe that such cases could be reclassified within the melanocytosis or melanomatosis spectrum, according to current classification15,41. 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 exon15, observed in 25% of DNA extracted from skin (50% cellularity) and in a small amount (1%) of DNA extracted from CNS lesion (30% cellularity).

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 studies30,42, 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.

 Acknowledgment: We sincerely thankful to Dr. Emanuela Tomacelli for editing the paper's linguistic revision.

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