Atypical neurofibromas reveal distinct epigenetic features with proximity to benign peripheral nerve sheath tumor entities

Abstract

Background Plexiform neurofibromas can transform into atypical neurofibromas (ANF) and then further progress to aggressive malignant peripheral nerve sheath tumors (MPNST). ANF have been described to harbor distinct histological features and frequent loss of CDKN2A/B. However, histological evaluation may be rater-dependent, and detailed knowledge about the molecular mechanisms of malignant transformation is scarce. In general, malignant transformation can be accompanied by significant epigenetic changes, and global DNA methylation profiling is able to differentiate relevant tumor subgroups. Therefore, epigenetic profiling might provide a valuable tool to distinguish and characterize ANF with differing extent of histopathological atypia from neurofibromas and MPNST. Methods We investigated 40 tumors histologically diagnosed as ANF and compared their global methylation profile to other peripheral nerve sheath tumors. Results Unsupervised class discovery and t-SNE analysis indicated that 36/40 ANF cluster with benign peripheral nerve sheet tumors with clear separation from MPNST. 21 ANF formed a molecularly distinct cluster in proximity to schwannomas. Tumors in this cluster had frequent heterozygous or homozygous loss of CDKN2A/B and significantly more lymphocyte infiltration than MPNST, schwannomas, and NF. Few ANF clustered closely with neurofibromas, schwannomas, or MPNST, raising the question, whether diagnosis based on histological features alone might pose a risk to both over- and underestimate the aggressiveness of these lesions. Conclusions Our data suggest that ANF with varying histological morphology show distinct epigenetic similarities and cluster in proximity to benign peripheral nerve sheath tumor entities. Future investigations should pay special respect to correlating this methylation pattern to clinical outcome.

Case report: Atypical neurofibromatous neoplasm with uncertain biological potential of the sciatic nerve and a widespread arteriovenous fistula mimicking a malignant peripheral nerve tumor in a young patient with neurofibromatosis type 1

“…Based on these findings and in line with current diagnostic criteria (3,14), we diagnosed an atypical neurofibromatous neoplasm with uncertain biological potential (ANNUBP). ANNUBP's often cluster with schwannomas in methylation analysis and harbor CDKN2A/B deletions (14,15). Adjuvant aggressive treatment could be avoided by early diagnosis and complete resection.…”

Cancer Predisposition Syndromes in Neuro-oncology

“…Although the biologic mechanism of malignant transformation is unclear, Cdkn2ab loss has been proposed as an initial step. 18 19…”

Past, Present, and Future Therapeutic Strategies for NF-1-Associated Tumors

“…Patients with NF-1 are at significantly increased risk for plexiform neurofibromas (PNs), a benign peripheral nervous system tumor that can transform into malignant peripheral nerve sheath tumors (MPNSTs), and low-grade gliomas (LGGs), a benign central nervous system tumor that can transform into malignant high-grade gliomas (HGGs) [ 8 – 10 ]. In addition, atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) comprise an intermediate tumor entity that reflect the transition from plexiform neurofibromas to MPNSTs [ 11 ]. ANNUBPs are associated with CDKN2AB loss, and their diagnosis and classification remain an area of active investigation [ 12 •, 13 , 14 ].…”