Melanocytic cells are normally found in the meninges of the central nervous system (CNS). They are numerous only on the ventral aspect of the lower part of the medulla oblongata, and a slight pigmentation is macroscopically visible in this region [2]. Diffuse or circumscribed primary leptomeningeal melanocytic neoplasms derived from meningeal melanocytic cells are rare [3].
According to the 2021 edition of the World Health Organization (WHO) classification of tumors of the CNS, diffuse lesions are characterized by the involvement of large expanses of the subarachnoid space with or without focal nodularity. Based on whether the lesion has benign (diffuse or multifocal meningeal proliferation of cytologially bland melanocytic cells) or malignant histological phenotype (diffuse or multifocal meningeal proliferation of melanoma cells with invasion of CNS parenchyma and/or marked cytological atypia and /or mitotic activity and/or necrosis), it is called meningeal melanocytosis or meningeal melanomatosis, respectively [4].
Circomscribed neoplasms may be designated as melanocytomas if they are benign or melanomas if they are malignant. Intermediate-grade lesions are also designated as melanocytomas.
Usually, all meningeal melanocytic tumors strongly express PS100, Melan A, HMB45 and MITF [5].
On histology, meningeal melanoma is accompanied by marked cytological atypia, increased mitotic activity > 1,5 mitoses/mm2 and often demonstrated unequivocal invasion of the CNS parenchyma or coagulative necrosis. It may be composed of pleomorphic spindled or epitheloid cells (arranged in loose nests, fascicles or sheets) and display variable cytoplasmic melanin.
Some meningeal melanomas contain large cells with bizarre nuclei, numerous mitotic figures and large nucleoli [5].
Others meningeal melanomas –such as our case- are highly cellular and less pleomorphic and usually consisting of smaller, tightly packed spindle cells. This histological aspect can be a challenge for the pathologist and must be distinguished from melanocytoma which is a benign tumor and lack cytological atypia, necrosis and mitoses (on average < 0,5 mitoses/mm2, equating to < 1mitosis/10 HPF of 0,5mm in diameter and 0, 2 mm2in area). Melanocytoma do not show invasion of CNS parenchyma. In the cases where a histological melanocytoma shows CNS invasion or increased mitotic activity (0,5 − 1,5 mitoses/mm2, equating to 1–3 mitoses/ 10 HPF of 0,5mm in diameter and 0,2 mm2in area) and no necrosis, the tumor is defined as Intermediate-grade Melanocytoma [5]. Cases of malignant transformation of melanocytoma into melanoma are described in the literature but are rare and occur especially after recurrence [6, 7].
Through the WHO description, we deduce the diagnostic value of tumor necrosis and mitotic activity to classify these tumors.
Another aspect of diagnostic difficulty encountered with meningeal melanoma is to confirm its primitive character and to distinguish it from other cerebral pigmented neoplasms.
Primary CNS melanoma is generally diagnosed following the exclusion of a primary cutaneous or mucosal/retinal melanoma, as differential histological diagnosis between primary and metastatic origins is often difficult [8, 9].
A metastasis from of cutaneous melanoma is the most likely of the differential diagnoses. Primary tumor is known in 90% of patients with secondary lesions and 45% of these have radiological evidence of multiple lesions; nevertheless, the primary tumor is unknown in 10% of the cases [3].
In addition of Meningeal Melanocytoma described above, the other differential diagnoses are represented by Meningioma which can have similar neuroradiologic findings and may mimic cerebral melanoma (hyperdense enhancing lesion on CT, in contact with the skull and dura mater). The differential diagnosis is more difficult in some cases of meningioma with cells containing melanin pigment; in this case, the immunohistochemical positivity of Somatostatin Receptor 2a, EMA and Progesterone Receptor is in favor of meningioma [3].
The distinction between meningeal melanoma and other melanotic tumors of the central nervous system such as Melanotic schwannoma - which has a similar immuoprofile to that of melanoma - can be a challenge [3]. Melanotic schwannoma is favored over malignant melanoma if features psammoma bodies and adipose-like cells, has cells with benign or mildly atypical cytology, and demonstrates evidence of pericellular basement membrane synthesis [10].
Mutation analysis (including for GNAQ, GNA11PLCB4 and CYSLTR2) and methylation profiling are useful for recognizing meningeal melanoma as primary CNS tumor and discriminating them from another pigmented CNS tumor.
Primary leptomeningeal melanocytic neoplasms have a molecular profile that is distinct from cutaneous melanomas and more closely resembles that of uveal melanomas and blue nevi. Cutaneous melanomas most frequently harbor activating mutations of the BRAF gene, NRAS or TERT promoter mutations [11].
Both benign and malignant circumscribed CNS melanocytic lesions harbor activating mutations in either the GNAQ or GNA11 genes. The presence of GNAQ or GNA11 mutation in the absence of a uveal melanoma or a blue naevus-like melanoma strongly favors a primary meningeal melanoma [5].
Because of the limited number of primary leptomeningeal melanocytic lesions analyzed, other mutations are less well characterized [11].
The survival for melanoma diagnosis with leptomeningeal involvement is poor. It is known that there are no specific guidelines for the management of both the primary CNS melanomas and leptomeningeal melanomatosis as they are rarely seen. However, radiotherapy, especially after surgical resection of a primary tumour, systemic chemotherapy with agents such as dacarbazine, cisplatin, thalidomide or temozalamid or intrathecal therapy with methothraxate, cytarabine and sometimes immunmodulatory agents such as peginterferon alpha-2b have all been used as treatments [12, 13].
The prognosis and life expectancy for patients with primary leptomeningeal melanoma associated with melanomatosis is worse despite treatment. Most authors quote a median survival of less than one year [14].
In conclusion, Meningeal melanomas present poor prognosis, partly due to their high rate of misdiagnosis.
This case highlights the diagnostic pitfalls encountered by the pathologist during the analysis of leptomeningeal melanocytic neoplasms. We insist on the importance of the histological interpretation to classify these tumors, in the absence of clinical, radiological and immunohistochemical specificity.
In some cases, mutation analysis (including for GNAQ, GNA11PLCB4 and CYSLTR2) and methylation profiling are useful for recognizing the diagnosis of primary meningeal melanoma.