Consensus recommendations for an integrated diagnostic approach to peripheral nerve sheath tumors arising in the setting of Neurofibromatosis type 1 (NF1)

Calixto-Hope G Lucas; Andrea M Gross; Carlos G Romo; Carina A Dehner; Alexander J Lazar; Markku Miettinen; Melike Pekmezci; Martha Quezado; Fausto J Rodriguez; Anat Stemmer-Rachamimov; David Viskochil; Arie Perry; Symposium on Atypical Neurofibroma: State of the Science Members

doi:10.1093/neuonc/noae235

Consensus recommendations for an integrated diagnostic approach to peripheral nerve sheath tumors arising in the setting of Neurofibromatosis type 1 (NF1)

Neuro Oncol. 2024 Nov 6:noae235. doi: 10.1093/neuonc/noae235. Online ahead of print.

Authors

Calixto-Hope G Lucas^{1

2

3}, Andrea M Gross⁴, Carlos G Romo^{2

5

6}, Carina A Dehner⁷, Alexander J Lazar⁸, Markku Miettinen⁹, Melike Pekmezci^{10

11}, Martha Quezado⁹, Fausto J Rodriguez¹², Anat Stemmer-Rachamimov¹³, David Viskochil¹⁴, Arie Perry^{10

15}; Symposium on Atypical Neurofibroma: State of the Science Members

Affiliations

¹ Department of Pathology, Johns Hopkins University, Baltimore, MD.
² Department of Oncology, Johns Hopkins University, Baltimore, MD.
³ Department of Neurosurgery, Johns Hopkins University, Baltimore, MD.
⁴ Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.
⁶ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
⁷ Department of Pathology, Indiana University, Indianapolis, Indiana.
⁸ Department of Pathology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
⁹ Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD.
¹⁰ Department of Pathology, University of California San Francisco, San Francisco, CA.
¹¹ Department of Ophthalmology, University of California San Francisco, San Francisco, CA.
¹² Department of Pathology, University of California Los Angeles, Los Angeles, CA.
¹³ Department of Pathology, Massachusetts General Hospital, Boston, MA.
¹⁴ Department of Pediatrics, University of Utah, Salt Lake City, UT.
¹⁵ Department of Neurological Surgery, University of California San Francisco, San Francisco, CA.

PMID: 39500722
DOI: 10.1093/neuonc/noae235

Abstract

Consensus recommendation 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 to 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 non-cutaneous 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.