Cutaneous malignant melanoma and neurofibromatosis type 1

Abstract

Neurofibromatosis 1 (NF1) is a genetically transmitted disease occurring approximately once in 3000 live births and resulting from mutations of the NF1 gene that encodes a protein named neurofibromin, a negative regulator of the ras-dependent pathway. An excess of neoplasia especially tumours of neuroectodermal origin is classically observed. The occurrence of malignant melanoma in patients with NF1 has already been described in scattered clinical reports but little is known as to the characteristics of melanoma arising in NF1 patients. A multicentric retrospective study was conducted on a panel of French referring centres for a period of 13 years to identify patients with both melanoma and NF1. Patients with mucosal or ocular melanoma were excluded. The diagnosis of malignant melanoma was based on specific histology whereas NF1 was identified according to the criteria proposed by the NIH Consensus Conference. All patient fulfilling criteria for both melanoma and NF1 were investigated using a common procedure recording clinical and histological data along with prognostic factors for the two diseases. Eleven patients were identified with both diseases. The clinical pattern of NF1 was quite similar to the classical form of the disease, but some unusual features were present as regards to the melanoma: a sex-ratio of 10 women for one man and an average age lower than expected (median age=33 years) for melanoma occurrence. Among prognostic factors, median thickness was high compared to large series of melanoma in the literature (3.20 versus 1.5 mm). Another neoplasia occurred in three patients. An increase in melanoma incidence in patients with NF1 remains hypothetical but our small series of malignant melanoma arising in NF1 patients displays a large female preponderance, a higher thickness than expected and a frequent association with a second neoplasia. The peculiar female proneness for cancer whatever its localization and the risk of multiple neoplasias have already been reported in NF1 patients and could be true for malignant melanoma as well.

The NF1 gene in tumor syndromes and melanoma

“…Based on a study of 11 NF1 patients with melanoma, a female preponderance, a higher thickness, and a frequent association with a second neoplasia were identified 17 . Additionally, a desmoplastic melanoma, a subtype of melanoma sharing some morphologic features with MPNST, has been reported in one individual with NF1 18 .…”

Genetic risk factors for melanoma

“…While convenient for academic discussion, this distinction is arbitrary and does not reXect that the risk imposed by inherited genetic factors represents a broad continuum and there is likely to be some overlap between the two tiers. A number of human syndromes are associated with an elevated incidence of melanoma, including retinoblastoma (Fletcher et al 2004), Werner syndrome (Goto et al 1996), xeroderma pigmentosum (Kraemer et al 1994) and neuroWbromatosis (Guillot et al 2004). These syndromes and the genes involved have been reviewed elsewhere (de Snoo and Hayward 2005) and will not be considered further here.…”

Glial versus melanocyte cell fate choice: Schwann cell precursors as a cellular origin of melanocytes

“…In addition, approximately 10% of plexiform neurofibromas undergo malignant transformation [129]. Other primary features are the associated abnormal pigmentary defects and the higher incidence of simultaneous occurrence of malignant melanoma [130][131][132]. Genetic studies on mosaic inactivation of the NF1 gene (neurofibromin) in several patients with NF1 disease identified SC as the major tumorigenic cell type.…”