青年男性软脑膜强化：原发性弥漫性软脑膜黑色素细胞肿瘤（NRAS/EIF1AX，介于黑色素细胞增生症与黑色素瘤病之间）Enhancement of the leptomeninges in a young man

Virtual glass slide

Box 1. Access at https://isn-slidearchive.org/?col=ISN&fol=Archive&file=20260528.svs.

Clinical history and imaging

This case involves a 22-year-old male with a past medical history significant for hypertension, who was transferred from an outside hospital on investigation of multiple prior nontraumatic subarachnoid hemorrhages and status epilepticus. Initial non-contrast computed tomography (CT) revealed increased sulcal density primarily in the bilateral frontal lobes mimicking a subarachnoid hemorrhage (Figure 1A). Subsequent brain magnetic resonance imaging (MRI) revealed T1 intrinsic hyperintensity of the bilateral cerebral sulci with diffuse superimposed leptomeningeal enhancement along the sulci, surface of the brainstem, cranial nerves, and ventricular margins (Figure 1B). A left frontal craniotomy was pursued for biopsy and definitive diagnosis. Intraoperatively, after the dura was opened, a dark, tar-like appearance involving the surface of the brain was visualized. Lesional tissue was obtained and sent for pathological analysis.

Findings

Histological analysis of the H&E-stained sections demonstrated a diffuse leptomeningeal proliferation of highly pigmented epithelioid melanocytic cells with moderate to severe nuclear atypia and infrequent mitotic figures (Figure 2A,C, Box 1). Necrosis was absent. Extension into the Virchow-Robin spaces without definitive parenchymal invasion was noted (Figure 2B). Immunohistochemistry staining revealed the tumor cells to be positive for Melan-A with preserved nuclear BAP1 expression. Clinically, the patient did not have a history of cutaneous melanoma or neurocutaneous syndrome.

Next-generation sequencing revealed an activating NRAS p.Gln61His (Q61H) mutation and a hotspot EIF1AX p.Gly8Arg mutation in exon 1. Whole genome methylation profiling was performed with a composite methylation profile listed as “No Match.” The corresponding copy number plot revealed a shallow gain of chromosome 8 and shallow deletions of 9q and 11q (focal), while 9p21 (CDKN2A/B) and 3p appeared intact.

Given the concerning imaging findings of a diffuse leptomeningeal process, and by applying the Central Nervous System-World Health Organization (CNS-WHO) framework, diffuse primary leptomeningeal melanocytic neoplasms (PLMNs) are classified as melanocytosis (benign) or melanomatosis (malignant) based on atypia, mitotic activity, invasion, and necrosis. In this case, the lesion displayed nuclear atypia and exceeded the cytologic blandness expected for classic meningeal melanocytosis. However, the low mitotic activity and lack of necrosis made the lesion fall short of overt melanomatosis. Histologically, this placed the lesion within a borderline zone between melanocytosis and melanomatosis.

The combination of clinical history, radiological findings, tumor morphology, and molecular findings was determined to be more consistent with a PLMN than with a conventional metastatic cutaneous melanoma. Overall, the findings support a borderline diffuse leptomeningeal melanocytic neoplasm, NRAS- and EIF1AX-mutant, with potential for aggressive behavior.

Final diagnosis

Primary diffuse leptomeningeal melanocytic neoplasm, NRAS and EIF1AX-mutant, borderline between melanocytosis and melanomatosis.

Discussion

Primary melanocytic tumors involving the CNS represent a spectrum of very rare tumors that can be classified as either malignant or benign. These tumors can present clinically as either a focally well-circumscribed lesion or a diffuse lesion with widespread involvement along the leptomeninges. As defined by the most recent 2021 CNS-WHO tumor classification system, meningeal melanocytosis is a diffuse or multifocal meningeal proliferation of cytologically bland melanocytic cells, while meningeal melanomatosis is a diffuse or multifocal meningeal proliferation of melanotic cells that often show invasion into the CNS parenchyma. Both entities arise from native leptomeningeal melanocytes derived from neural crest cells.

From an epidemiological standpoint, diffuse meningeal melanocytic neoplasms are very rare, making population-based studies challenging to assess and quantify. These tumors have been reported to occur in both adults and children. Melanocytosis primarily affects children in the setting of neurocutaneous melanosis (NCM). Melanomatosis often exhibits a bimodal age distribution and may manifest in children, with or without NCM, and in adults predominantly in the 4th decade of life.

It has been proposed, in a study by Kinsler et al., that the pathogenesis involving meningeal melanomatosis and melanocytosis is predominately associated with postzygotic mutations in the NRAS gene at codon 61, which results in an initial genetic insult via proto-oncogene activation where the NRAS gene acts as a primary driver in a multi-step oncogenic process. The NRAS gene is an important member of the RAS GTPase family that primarily regulates cellular proliferation, differentiation, and survival involving the RAF/MEK/ERK and PI3K/mTOR pathways.

The present case also showed an EIF1AX p.Gly8Arg mutation in exon 1. According to a study by Küsters-Vandevelde et al., detection of missense mutations involving EIF1AX (exon 1 and 2 and flanking intronic regions) was found to occur at a relatively high frequency (~21%) in PLMNs. These mutations were also observed generally co-occurring with GNAQ, GNA11, and NRAS mutations, suggesting that the EIF1AX mutations arise later in the tumorigenesis pathway.

This interesting case demonstrates a rare tumor with unique histological features where significant overlap was observed between melanocytosis and melanomatosis. The tumor could not be placed in either category, making it a rare borderline diffuse leptomeningeal melanocytic neoplasm, NRAS- and EIF1AX-mutant, with potential for aggressive behavior.