Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations

Abstract

Optic pathway glioma (OPG), seen in 15% to 20% of individuals with neurofibromatosis type 1 (NF1), account for significant morbidity in young children with NF1. Overwhelmingly a tumor of children younger than 7 years, OPG may present in individuals with NF1 at any age. Although many OPG may remain indolent and never cause signs or symptoms, others lead to vision loss, proptosis, or precocious puberty. Because the natural history and treatment of NF1-associated OPG is different from that of sporadic OPG in individuals without NF1, a task force composed of basic scientists and clinical researchers was assembled in 1997 to propose a set of guidelines for the diagnosis and management of NF1-associated OPG. This new review highlights advances in our understanding of the pathophysiology and clinical behavior of these tumors made over the last 10 years. Controversies in both the diagnosis and management of these tumors are examined. Finally, specific evidence-based recommendations are proposed for clinicians caring for children with NF1.

Figure 1. Location and MRI characteristics of NF1-optic pathway gliomas (OPGs)

(A) Axial T2-weighted MRI scan depicts a normal optic chiasm and optic nerves (ONs) in a child with NF1 lacking an OPG. (B) Axial T2-weighted MRI scan shows an OPG in a child with NF1 involving the optic chiasm and nerves. The chiasm is enlarged and diffusely hyperintense. The optic nerves show fusiform enlargement and tortuosity bilaterally (arrowheads). (C) Axial T1-weighted non-contrast MRI scan in a different child with NF1 with an OPG involving the optic radiations (asterisks).

Figure 2. RAS effector pathway de-regulation underlies optic pathway glioma (OPG) growth and tumor-associated retinal ganglion cell (RGC) dysfunction

Neurofibromin is a negative regulator of the RAS proto-oncogene product. It accelerates the conversion of active RAS-GTP to inactive GDP-bound RAS. (A) In tumor cells with biallelic NF1 inactivation (NF1-deficient cells), there is increased activation of the MEK-ERK and PI3K-AKT-mTOR pathways, resulting in greater cell proliferation and survival. RAS hyperactivation also leads to decreased cyclic AMP (cAMP) levels to promote tumor cell survival. (B) In RGCs heterozygous for a germline NF1 gene mutation (NF1-mutant cells), impaired neurofibromin function leads to reduced adenylyl cyclase-mediated cAMP production and increased RGC death. Based on mechanistic studies in other CNS neurons, the reduced cAMP in RGCs likely results from increased RAS-dependent activation of protein kinase C-ζ (PKCζ).

Figure 3. Cell-autonomous and cell-non-autonomous mechanisms underlying optic pathway glioma pathogenesis and associated vision loss

(A, B) Sagittal sections through the mammalian eye (A) and retina (B). Photoreceptor (cone and rod) afferent pathways converge on retinal ganglion cells (RGCs). RGC bodies reside in the ganglion cell layer (GCL) of the retina, and their axons course through the retinal nerve fiber layer (RNFL) into the optic nerve. (C) In NF1-mutant RGCs, impaired neurofibromin function reduces intracellular cAMP levels, thereby lowering the threshold for RGC death and subsequent vision loss. (D) NF1-mutant microglia secrete chemokines (e.g., CCL5, CXCL12), which promote the proliferation and survival of NF1-deficient tumor cells. In addition, estrogen receptor β (ERβ)-mediated microglial priming leads to the production of neurotoxins (e.g., IL-1β) that increase NF1-mutant RGC axonal dysfunction and death, causing vision loss in a sex-dependent manner. Tan-colored cells denote NF1-mutant oligodendrocytes that ensheath the optic nerve axons. The gray arrows indicate potential intercellular interactions in NF1-OPG, which are described in the main text.