Abstract
NF1-associated nerve sheath tumors exist on a morphologically and molecularly diverse spectrum. Criteria for diagnosing neurofibroma, atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP), and malignant peripheral nerve sheath tumor (MPNST) developed by consensus in 2017 were codified in recent WHO guidelines. However, incorporation of molecular strata should be formalized to aid in early identification and appropriate intervention for patients with lesions at increased risk for malignant transformation. Here, we assembled a multi-institutional expert pathology working group to review molecular literature and formalize classification recommendations. In collaboration with clinical/surgical, imaging, and pre-clinical working groups during the “Symposium on Atypical Neurofibroma: State of the Science” held April 2024, we reached consensus on a potential integrated diagnostic approach. Based on strong preclinical and clinical evidence, we propose CDKN2A homozygous deletion as a sufficient molecular feature for diagnosing ANNUBP and either SUZ12, EED, or TP53 inactivating mutations or significant aneuploidy as sufficient molecular features for diagnosing MPNST, even in the absence of high-grade histologic features. In the absence of MPNST-defining molecular alterations, we also recommend reclassifying “low grade MPNST” as “ANNUBP with increased proliferation”. To facilitate molecular characterization of concerning tumors, we recommend at least six core biopsies be obtained and divided into two cores per block at time of grossing. Worrisome immunohistochemical features including reduced SOX10 or S100 immunoreactivity, decreased CD34 lattice-like network, minimal p16 expression, loss of H3K27me3 immunoreactivity, p53 overexpression, and increased Ki-67 labeling can guide region selection. A comprehensive next-generation sequencing panel that includes copy number and zygosity assessment is the preferred single assay, though a combination of multiple molecular techniques may provide similar information. In the spirit of the prior 2017 consensus agreement, we hope this refined integrated diagnostic approach for NF1-associated nerve sheath tumors will continue to evolve alongside our understanding of the spectrum of these neoplasms.