Clinical, Radiological, Histologic and Molecular Features of a Cohort of Melanocytic Tumors of the Central Nervous System

Overview

Primary melanocytic tumors of the central nervous system are rare lesions and occur develop from leptomeningeal melanocytes. The WHO classification of tumors of the central nervous system in its most recent version (2021) distinguishes on the one hand the circumscribed melanocytic tumors including melanocytoma, benign, and its slope malignant, meningeal melanoma, with an intermediate grade lesion in between, called intermediate grade melanocytoma. They are to be distinguished from diffuse tumors or multifocal diseases such as melanocytosis and its malignant corollary, melanomatosis. The main current challenge is to distinguish them from their differential diagnoses, namely metastasis of a cutaneous or extrac-cutaneous melanoma mainly and on the other hand other pigmented entities occuring in the CNS such as malignant melanic tumor of the peripheral nerve sheath (MMNST, formerly "melanotic schwannoma").

The discovery within the CNS of a tumor of melanocytic nature requires the realization an exhaustive assessment (dermatological examination, whole body imaging), especially in the event of signs histological evidence of malignancy (marked atypia, mitoses, infiltration of the parenchyma), in order to look for unnoticed cutaneous melanoma. In the absence of primary lesion found outside the nervous system, the question of a primary lesion with a meningeal starting point arises. A molecular characterization is then required, in order to highlight mutations recurrent spores of the GNA11 or GNAQ genes, classically not found in the cutaneous melanomas, the latter presenting different genetic alterations (BRAF, NRAS, KIT etc). Other rarer alterations such as PLCB4 or CYSLTR2 are also described in these meningeal melanocytic tumors, but are not part of the gene panels of routine. On the other hand, the discovery of a circumscribed melanocytic lesion, in particular intradural extramedullary and spindle cells, should suggest the differential diagnosis malignant melanotic nerve sheath tumor (MMNST, malignant melanotic nerve sheath tumor), formerly called "melanotic schwannoma". Distinguish them histologically can be tricky. This differential diagnosis is important, the MMNST entering often in the context of Carney syndrome, of autosomal dominant transmission, responsible for other conditions requiring multidisciplinary follow-up (cardiac myxoma, endocrine disorders). Recent advances in molecular biology have opened up new possibilities for the diagnosis and classification of brain tumours. One of them is the methylome, studying the epigenetic signature of a tumor via its methylation profile. These epigenetic modifications play an important role in regulating the expression genes and are now well known to be involved in the development and cancer progression. This tool has been integrated into the new WHO 2021 classification of CNS tumors and constitutes for certain entities an essential criterion for their diagnosis final. The publication by Capper et al. in 2018, entitled "DNA methylation-based classification of central nervous system tumours" illustrates this point. It was highlighted that meningeal melanocytic tumors cluster separately from other types of tumors, including cutaneous melanomas. Three methylation classes exist currently in version 12.5 of the classifier developed by the University of Heidelberg (www.molecularneuropathology.com): a class of methylation specific to the metastases of melanoma, one for malignant melanotic peripheral nerve sheath tumors, and a titled melanocytoma (which includes entities with similar profiles: melanocytoma and meningeal melanoma but also uveal melanoma). He does not exist to date of methylation class for diffuse meningeal melanocytic tumors(melanocytosis and its malignant corollary melanomatosis). To conclude, meningeal melanocytic tumors are a group of tumors of the system central nervous system rare but for which it is necessary to make a diagnosis of certainty The WHO classification proposed in 2021 is based on an integrative histo-molecular approach, but for which the community medicine still lacks perspective. In particular, when using this new classification, it there are difficulties in classifying certain tumours, presenting clinical aspects, discordant radiological, histopathological and molecular findings. The aims of this study are therefore to classify melanocytic tumors according to the new WHO 2021 classification of central nervous system tumors, to describe their clinical, radiological, histological and molecular characteristics, to define new prognostic criteria (mitotic index, Ki-67 , immunohistochemical markers such as BAP1 and p16) and to establish clinico-radio-histo-molecular correlations.