Consensus recommendations for an integrated diagnostic approach to peripheral nerve sheath tumors arising in the setting of Neurofibromatosis Type 1

Abstract

Consensus recommendations published in 2017 histologically defining atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP) and malignant peripheral nerve sheath tumor (MPNST) were codified in the 2021 WHO Classification of Tumors of the Central Nervous System and the 2022 WHO Classification of Tumors of Soft Tissue and Bone. However, given the shift in diagnostic pathology toward the use of integrated histopathologic and genomic approaches, the incorporation of additional molecular strata in the classification of Neurofibromatosis Type 1 (NF1)-associated peripheral nerve sheath tumors should be formalized to aid in accurate diagnosis and early identification of malignant transformation and enable appropriate intervention for affected patients. To this end, we assembled a multi-institutional expert pathology working group as part of a "Symposium on Atypical Neurofibroma: State of the Science." Herein, we provide a suggested framework for adequate interventional radiology and surgical sampling and recommend molecular profiling for clinically or radiologically worrisome noncutaneous lesions in patients with NF1 to identify diagnostically-relevant molecular features, including CDKN2A/B inactivation for ANNUBP, as well as SUZ12, EED, or TP53 inactivating mutations, or significant aneuploidy for MPNST. We also propose renaming "low-grade MPNST" to "ANNUBP with increased proliferation" to avoid the use of the "malignant" term in this group of tumors with persistent unknown biologic potential. This refined integrated diagnostic approach for NF1-associated peripheral nerve sheath tumors should continue to evolve in concert with our understanding of these neoplasms.

Keywords: consensus; guidelines; molecular neuropathology; nerve sheath tumor; neurofibromatosis type 1.

Figure 1.

An integrated diagnostic approach for NF1-associated peripheral nerve sheath tumors. (A) Integration of histologic and molecular features would result in reclassification of a subset of tumors with neurofibroma histology but also harboring CDKN2A/B homozygous deletion or inactivation as ANNUBP and another subset of tumors with either neurofibroma or ANNUBP histology but also harboring SUZ12, EED, TP53 mutations, or significant aneuploidy as MPNST. (B) A case previously diagnosed as a plexiform neurofibroma based on histologic features at the time of resection was found to harbor CDKN2A/B homozygous deletion on sequencing and would be reclassified as an ANNUBP. (C) A case previously diagnosed as ANNUBP on core biopsy was found to harbor a clonal SUZ12 frameshift mutation as well as multiple segmental chromosomal gains and losses and would be reclassified as a MPNST. CDKN2A/B homozygous deletion is also noted in this case but is not required for the diagnosis of MPNST. Scale bars, 100 µm. ANNUBP = atypical neurofibromatous neoplasm of uncertain biologic potential; MPNST = malignant peripheral nerve sheath tumors; NF1 = neurofibromatosis type 1.

Figure 2.

Worrisome immunohistochemical features in NF1-associated peripheral nerve sheath tumors. While difficult to assess on core biopsy specimens, CD34 immunohistochemistry is useful in highlighting the presence of a lattice-like network in a neurofibroma. This network is typically lost in adjacent areas transitioning to ANNUBP and MPNST. Even on core biopsies, decreased expression of S100 and SOX10 is worrisome for a higher-grade lesion, as these markers are typically extensively expressed in neurofibroma. Loss of p16 expression may correlate with underlying CDKN2A/B homozygous deletion, and loss of H3K27me3 may correlate with underlying alterations to PRC2 proteins such as SUZ12 or EED. Increased immunoreactivity for p53 may also raise concern. Scale bars, 100 µm. ANNUBP = atypical neurofibromatous neoplasm of uncertain biologic potential; MPNST = malignant peripheral nerve sheath tumors; NF1 = neurofibromatosis type 1; PRC2 = polycomb repressive complex 2.