Management of neurofibromatosis type 1-associated plexiform neurofibromas

Abstract

Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment options limited historically to surgery. There have been tremendous advances over the past two decades in our understanding of PN, and the recent regulatory approvals of the MEK inhibitor selumetinib are reshaping the landscape for PN management. At present, there is no agreed upon PN definition, diagnostic evaluation, surveillance strategy, or clear indications for when to initiate treatment and selection of treatment modality. In this review, we address these questions via consensus recommendations from a panel of multidisciplinary NF1 experts.

Keywords: MEK inhibitor; neurofibroma; neurofibromatosis 1; plexiform; review.

Fig. 1

Proposed plexiform neurofibroma classification schema. For each tumor, determine classification in each category (A–C, D optional).

Fig. 2

MRI examples of plexiform neurofibromas (PN) demonstrating tumor characteristics used in the proposed classification schema. All images are fat suppressed with STIR (short tau inversion recovery) technique. (A) The internal structure can be homogeneous without notable architectural elements (left panel, solid arrow), appear as conglomerate of small nodules (right panel, dotted arrows), or show a combination of both features (middle panel). (B) Any portion of peripheral nerves may be affected by PN. Proximal nerve segments give rise to deep internal PN (left panel, dotted arrows), superficial PN (right panel, solid arrows) are associated with terminal nerve branches, but many lesions have components of both (middle panel). (C) The interface between PN and surrounding tissues can range from interdigitating and intricately connected (left panel, solid arrows) to sharply defined and well separated (right panel, dotted arrows), with most lesions falling in between those two extremes (middle panel).

Fig. 3

Coronal (top row) and axial (bottom row) STIR MRI examples of distinct nodular lesions (DNL) in patients with NF1. The left panels show a DNL (arrow) arising from the left sciatic nerve. In the middle panels, plexiform neurofibroma (PN) can be seen along the brachial plexus on both sides, with a prominent nodule present on the right (arrow). On the right, the DNL (arrow) stands out from the background of a large neck, shoulder, and chest PN.

Fig. 4

Tumor growth rate plotted against patient’s age at initial MRI for plexiform neurofibromas (PN) (A) and distinct nodular lesions (DNL) (B). A moderate negative correlation was observed for PN, whereas only a weak association was noted for DNL. Adapted from Akshintala S, et al. Neuro Oncol. 2020.Reprinted with permission.

Fig. 5

Longitudinal assessment of plexiform neurofibroma (PN) size using volumetric MRI analysis. While the longest diameter of the left flank lesion remained almost the same over time, the bulk of the PN increased visibly between 4.9 years and 6.6 years of age, at which point the patient started selumetinib therapy resulting in PN shrinkage. Volumetric analysis is performed by identifying tumor contours as shown by the outlines in the bottom panels. This technique allows to detect small changes sensitively and reproducibly.