Contemporary Approach to Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors

Abstract

Most malignant peripheral nerve sheath tumors (MPNSTs) are clinically aggressive high-grade sarcomas, arising in individuals with neurofibromatosis type 1 (NF1) at a significantly elevated estimated lifetime frequency of 8%-13%. In the setting of NF1, MPNSTs arise from malignant transformation of benign plexiform neurofibroma and borderline atypical neurofibromas. Composed of neoplastic cells from the Schwannian lineage, these cancers recur in approximately 50% of individuals, and most patients die within five years of diagnosis, despite surgical resection, radiation, and chemotherapy. Treatment for metastatic disease is limited to cytotoxic chemotherapy and investigational clinical trials. In this article, we review the pathophysiology of this aggressive cancer and current approaches to surveillance and treatment.

Figure 1:. Biologic Progression from plexiform neurofibroma to malignant peripheral nerve sheath tumor.

This simplified model demonstrates the molecular changes that drive malignant transformation from precursor plexiform neurofibroma (PN, A) to atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP, B) to malignant peripheral nerve sheath tumor (MPNST, C). The initial hit is a biallelic inactivation of NF1 leading to a PN. This is followed by loss of CDKN2A/B and subsequently mutations involving the PRC2 (EED, SUZ12) and TP53 complex. Throughout this transition, there is gradual loss of S100 protein expression, loss of p16 expression (correlates with CDKN2A deletion) and eventually loss of H3K27me3 expression (correlates with EED/SUZ12 deletion).

Figure 2:. Development of MPNST from pre-existing neurofibroma

Axial fluid sensitive fat-suppressed magnetic resonance images of the pelvic region demonstrate the evolution of a small discrete neurofibroma at age 17.5 years (A) into an encapsulated larger distinct nodular lesion (DNL) by age 20.3 (B) and biopsy confirmed MPNST by age 21.1 (C). The malignant transformation is indicated by growth acceleration (D), change on the apparent diffusion coefficient (ADC) maps from ADCmin 1,488 mm²/s within the DNL (E) to 844 mm²/s within the MPNST (F), and high metabolic activity on ¹⁸F-fluorodeoxyglucose (FDG)-PET/CT with standard uptake value (SUV) of 28.1; PET acquisition (G), CT acquisition (H) and color-mapped PET/CT image fusion (I).