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

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

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").

Study Overview

• Status: Recruiting
• Conditions: Meningeal Melanocytoma; Meningeal Melanomatosis; Meningeal Melanocytosis; Meningeal Melanoma

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

Study Locations

• France
  • Nancy, France, 54500
    • Recruiting
    • Nancy University Hospital Center
    • Contact: Guillaume GAUCHOTTE, PhD; Phone Number: +33 3 83 65 60 17; Email: g.gauchotte@chru-nancy.fr
    • Contact: Emilie BECKER, MD; Phone Number: +33 3 83 65 60 17; Email: e.becker@chru-nancy.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with primitive meningeal melanocytic tumors

Description

Inclusion Criteria:

• Patient with a primitive meningeal melanocytic tumor

Exclusion Criteria:

• Patient with metastatic extrameningeal melanoma

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Meningeal melanocytoma
Meningeal melanoma
Meningeal melanomatosis
Meningeal melanocytosis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnosis according to WHO classification of CNS tumors (5th edition)	Histologic diagnosis according to WHO classification of CNS tumors (5th edition) among these 5 options : melanocytoma, intermediate-grade melanocytoma, melanoma, melanocytosis, melanomatosis	at baseline (initial report)
Mitotic index	Number of mitoses per square millimetre	at baseline (initial report)
Age	Age in years	At baseline
Sex	Male or female	At baseline
Ki-67	Proliferation index Ki-67, assessed by immunohistochemistry, counted on 500 cells	At time of initial diagnosis
T1-weighted sequence signal	Radiologic feature : tumor T1-weighted sequence signal on MRI (hyposignal, isosignal, hypersignal)	At time of initial diagnosis
Enhancement after gadolinium injection	Radiologic feature: tumor enhancement after gadolinium injection on MRI	At time of initial diagnosis

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Time from diagnosis to death	From date of initial diagnosis until the date of death of any cause assessed up to 10 years
Progression-free survival	Time from diagnosis to first progression	From date of initial diagnosis until the date of first documented progression assessed up to 10 years

Collaborators and Investigators

• Sponsor: Central Hospital, Nancy, France

Publications and helpful links

General Publications

• Koelsche C, Hovestadt V, Jones DT, Capper D, Sturm D, Sahm F, Schrimpf D, Adeberg S, Bohmer K, Hagenlocher C, Mechtersheimer G, Kohlhof P, Muhleisen H, Beschorner R, Hartmann C, Braczynski AK, Mittelbronn M, Buslei R, Becker A, Grote A, Urbach H, Staszewski O, Prinz M, Hewer E, Pfister SM, von Deimling A, Reuss DE. Melanotic tumors of the nervous system are characterized by distinct mutational, chromosomal and epigenomic profiles. Brain Pathol. 2015 Mar;25(2):202-8. doi: 10.1111/bpa.12228. Epub 2014 Dec 15.
• Kusters-Vandevelde HV, Kusters B, van Engen-van Grunsven AC, Groenen PJ, Wesseling P, Blokx WA. Primary melanocytic tumors of the central nervous system: a review with focus on molecular aspects. Brain Pathol. 2015 Mar;25(2):209-26. doi: 10.1111/bpa.12241.
• Griewank KG, Koelsche C, van de Nes JAP, Schrimpf D, Gessi M, Moller I, Sucker A, Scolyer RA, Buckland ME, Murali R, Pietsch T, von Deimling A, Schadendorf D. Integrated Genomic Classification of Melanocytic Tumors of the Central Nervous System Using Mutation Analysis, Copy Number Alterations, and DNA Methylation Profiling. Clin Cancer Res. 2018 Sep 15;24(18):4494-4504. doi: 10.1158/1078-0432.CCR-18-0763. Epub 2018 Jun 11.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: June 25, 2023
• First Submitted That Met QC Criteria: July 31, 2023
• First Posted (Actual): August 9, 2023

Study Record Updates

• Last Update Posted (Actual): August 9, 2023
• Last Update Submitted That Met QC Criteria: July 31, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms; Neoplasms by Site; Nervous System Neoplasms; Central Nervous System Neoplasms
• Other Study ID Numbers: 2022PI132

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No