Histopathologic Evaluation of Atypical Neurofibromatous Tumors and Their Transformation into Malignant Peripheral Nerve Sheath Tumor in Neurofibromatosis 1 Patients – A Consensus Overview

Publication date: Available online 24 May 2017
Source:Human Pathology
Author(s): Markku M. Miettinen, Cristina R. Antonescu, Christopher D.M. Fletcher, Aerang Kim, Alexander J. Lazar, Martha M. Quezado, Karlyne M. Reilly, Anat Stemmer-Rachamimov, Douglas R. Stewart, David Viskochil, Brigitte Widemann, Arie Perry
Neurofibromatosis 1 (NF1) patients develop multiple neurofibromas, with 8-15% of patients experiencing malignant peripheral nerve sheath tumor (MPNST) during their lifetime. Prediction of transformation, typically from plexiform neurofibroma, is clinically and histologically challenging. In this overview, following a consensus meeting in October 2016, we outline the histopathologic features and molecular mechanisms involved in the malignant trans-formation of neurofibromas. Nuclear atypia alone is generally insignificant. However, with atypia, loss of neurofibroma architecture, high cellularity, and/or mitotic activity >1/50 but <3/10 high power fields, the findings are worrisome for malignancy. We propose the term “atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP)” for lesions displaying at least two of these features. This diagnosis should prompt additional sampling, clinical correlation, and possibly, expert pathology consultation. Currently such tumors are diagnosed inconsistently as atypical neurofibroma or low-grade MPNST. Most MPNSTs arising from neurofibromas are high-grade sarcomas and pose little diagnostic difficulty, although rare non-necrotic tumors with 3-9 mitoses/10 HPFs can be recognized as low-grade variants. While neurofibromas contain numerous S100 protein/SOX10-positive Schwann cells and CD34-positive fibroblasts, both components are reduced or absent in MPNST. Loss of p16/CDKN2A expression, elevated Ki67 labeling, and extensive nuclear p53 positivity are also features of MPNST that can to some degree already occur in ANNUBP. Complete loss of trimethylated histone 3 lysine 27 (H3K27me3) expression is potentially more reliable, being immunohisto-chemically detectable in about half of MPNSTs. Correlated clinicopathologic, radiologic, and genetic studies should increase our understanding of malignant transformation in neurofibromas, hopefully improving diagnosis and treatment soon.



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