Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors

Abstract

Benign peripheral nerve sheath tumors (PNSTs) are a characteristic feature of neurofibromatosis type I (NF1) patients. NF1 individuals have an 8-13% lifetime risk of developing a malignant PNST (MPNST). Atypical neurofibromas are symptomatic, hypercellular PNSTs, composed of cells with hyperchromatic nuclei in the absence of mitoses. Little is known about the origin and nature of atypical neurofibromas in NF1 patients. In this study, we classified the atypical neurofibromas in the spectrum of NF1-associated PNSTs by analyzing 65 tumor samples from 48 NF1 patients. We compared tumor-specific chromosomal copy number alterations between benign neurofibromas, atypical neurofibromas, and MPNSTs (low-, intermediate-, and high-grade) by karyotyping and microarray-based comparative genome hybridization (aCGH). In 15 benign neurofibromas (4 subcutaneous and 11 plexiform), no copy number alterations were found, except a single event in a plexiform neurofibroma. One highly significant recurrent aberration (15/16) was identified in the atypical neurofibromas, namely a deletion with a minimal overlapping region (MOR) in chromosome band 9p21.3, including CDKN2A and CDKN2B. Copy number loss of the CDKN2A/B gene locus was one of the most common events in the group of MPNSTs, with deletions in low-, intermediate-, and high-grade MPNSTs. In one tumor, we observed a clear transition from a benign-atypical neurofibroma toward an intermediate-grade MPNST, confirmed by both histopathology and aCGH analysis. These data support the hypothesis that atypical neurofibromas are premalignant tumors, with the CDKN2A/B deletion as the first step in the progression toward MPNST.

Loss of H3K27 trimethylation distinguishes malignant peripheral nerve sheath tumors from histologic mimics

“…5,6 CDKN2A inactivation is an early event in the development of malignant peripheral nerve sheath tumor, occurring during progression from conventional to atypical neurofibroma. 5 In addition, inactivation of the polycomb repressive complex 2 (PRC2), resulting from mutually exclusive inactivating mutations of its constituents SUZ12 or EED1, was recently identified in 70-90% of malignant peripheral nerve sheath tumors. [6][7][8] PRC2 inactivation leads to loss of trimethylation at lysine 27 of histone H3 (H3K27me3).…”

Induction of mitotic catastrophe by PKC inhibition in Nf1-deficient cells

“…Genetic changes (such as the loss of the CDKN2A/B, encoded proteins of which are negative cell cycle regulators) could be detected at early stages of NF1. 44 In MPNSTs, the genes of p53 and other tumor suppressors are often mutated. In particular, under Nf1 deficient conditions, the expression and function of aurora kinase (a regulator of the mitosis) were upregulated to promote cell proliferation or migration, in a Ras-dependent fashion.…”

Management and Treatment of “Complex Neurofibromatosis 1”

“…Atypical neurofibromas are pleomorphic and hypercellular tumours, without evidence of mitosis, and they may have malignant potential, as both atypical neurofibromas and MPNST have chromosomal aberrations and are positive on FDG PET CT (Beert et al 2011;Ferner et al 2008). Persistent pain, rapid growth, hard texture or unexplained neurological deficit in association with a plexiform neurofibroma should prompt urgent referral and assessment in collaboration with specialist sarcoma units.…”