Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Sep:67:1-10.
doi: 10.1016/j.humpath.2017.05.010. Epub 2017 May 24.

Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1-a consensus overview

Markku M Miettinen  1 , Cristina R Antonescu  2 , Christopher D M Fletcher  3 , Aerang Kim  4 , Alexander J Lazar  5 , Martha M Quezado  6 , Karlyne M Reilly  7 , Anat Stemmer-Rachamimov  8 , Douglas R Stewart  9 , David Viskochil  10 , Brigitte Widemann  11 , Arie Perry  12
Affiliations
Review

Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1-a consensus overview

Markku M Miettinen et al. Hum Pathol. 2017 Sep.

Abstract

Patients with neurofibromatosis 1 (NF1) develop multiple neurofibromas, with 8% to 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, after a consensus meeting in October 2016, we outline the histopathologic features and molecular mechanisms involved in the malignant transformation 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 2 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 nonnecrotic tumors with 3-9 mitoses/10 high-power fields can be recognized as low-grade variants. Although 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 atypical neurofibromatous neoplasms of uncertain biologic potential. Complete loss of trimethylated histone 3 lysine 27 expression is potentially more reliable, being immunohistochemically detectable in about half of MPNSTs. Correlated clinicopathological, radiologic, and genetic studies should increase our understanding of malignant transformation in neurofibromas, hopefully improving diagnosis and treatment soon.

Keywords: Atypia; Malignant peripheral nerve sheath tumor; Neurofibroma; Neurofibromatosis 1; Transformation.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Development and growth of distinct nodules in a paraspinal retroperitoneal plexiform neurofibroma, as shown in successive MR images over a 6-year period. Three separate nodular growths are highlighted with red, yellow, and green arrows. Upper row is axial and lower sagittal projection.
Fig. 2
Fig. 2
A–C. Examples of plexiform neurofibromas with nuclear atypia (‘ancient neurofibromas’), but preserved neurofibroma architecture. D. Appearance of high cellularity here is caused by extensive lymphohistiocytic infiltration, obscuring neurofibroma architecture.
Fig. 3
Fig. 3
Cellular neurofibroma shows moderate cellularity with no other worrisome features. The Ki67 labeling index is < 3%. The tumor retains strong S100-positivity in the schwannian component and a well-developed CD34-positive fibroblastic network.
Fig. 4
Fig. 4
Histological appearances of atypical neurofibromatous tumors of uncertain biologic potential (ANNUBP). A. Tumor with loss of neurofibroma architecture and increased vascularity (not enough for ANNUBP by itself). B. Prominent nuclear atypia without high cellularity or mitoses (not enough for ANNUBP by itself). C. Increased cellularity with a fascicular pattern (loss of neurofibroma architecture), but without mitotic activity. D. Increased cellularity and mitotic activity.
Fig. 5
Fig. 5
Immunohistochemical findings of neurofibroma transitioning into low-grade MPNST A. S100 protein-positive Schwann cells are greatly reduced. B. CD34-positive fibroblastic network is also reduced. C. Ki67-labeling index is elevated, reaching close to 10%. D. Moderate numbers of nuclei are p53-positive.
Fig. 6
Fig. 6
Typical findings in a high-grade MPNST. A. Fibrosarcoma-like highly cellular spindled tumor with mitotic activity. B. Geographic necrosis with a perivascular sparing pattern (i.e., perivascular collections of tumor remain viable). C. Complex vascular proliferation and nuclear pleomorphism. D. Rhabdomyosarcomatous differentiation is seen in a minority of cases.
Fig. 7
Fig. 7
Immunohistochemical findings typical of a high-grade MPNST. A. Only a small number of slender S100-positive Schwann cells are present mostly representing elements of residual neurofibroma. B. This example shows Schwannian differentiation as demonstrated by extensive SOX10 positivity in tumor cells. C. Tumor cells have a loss of p16 expression, with non-neoplastic cells positive. D. There is a loss of expression of trimethylated lysine 27 in histone 3 (H3K27me3) in tumor nuclei. Lymphoid cells and endothelia serve as internal positive controls.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. 1997;278:51–7. - PubMed
    1. De Raedt T, Beert E, Pasmant E, et al. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014;514:247–251. - PubMed
    1. Lee W, Teckie S, Wiesner T, et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat Genet. 2014;46(11):1227–32. - PMC - PubMed
    1. Zhang M, Wang Y, Jones S, et al. Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. Nat Genet. 2014;46:1170–1172. - PMC - PubMed
    1. Evans DG, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002;39:311–4. - PMC - PubMed

Publication types

Substances

-