Chapter 34
Neurofibromatosis: Tumors of the Optic
Pathway
John M. Slopis and Jade S. Schiffman
Abstract Various tumors occur in patients with neurofibromatosis type 1. In this chapter, we discuss the clinical presentation and evaluation of four types of tumors affecting patients with neurofibromatosis type 1: periorbital and orbital neurofibroma, intraorbital optic nerve glioma, chiasmal and hypothalamic glioma, and intraparenchymal astrocytoma. Treatment options are also discussed.
34.1 Introduction
Neurofibromatosis (NF) is a common neurocutaneous disorder affecting approximately 1 in 4000 individuals [1]. NF is a group of genetic disorders that include NF type 1 (NF1), NF type 2 (NF2), and multiple schwannomatosis; each form of the disorder has different genetic mutations and pathologic bases. NF2 and multiple schwannomatosis are essentially disorders of the cranial nerves, peripheral nerves, and meningeal tissues and do not as commonly impact the optic pathway as NF1. This chapter will focus on NF1; therefore, NF2 and multiple schwannomatosis will be excluded from this discussion.
The NF1 gene coding region is a large gene segment localized to chromosome 17 [2, 3]. The NF1 gene is nearly ubiquitous in human tissues. The gene is expressed in fetal ectoderm, neuroectoderm, mesoderm, and neural crest tissues; thus, the NF1 gene impacts virtually all organ systems, including all components of the optic pathway. The NF1 gene codes the production of the protein neurofibromin, which is central to the growth and development of many tissues during fetal development and serves as a maintenance growth regulator for tissues after birth [4]. Mutations of this gene thus lead to congenital tumors and other structural malformations, as well as benign tumors of later onset that continue to grow throughout life.
The most common tumor caused by NF1 mutation is the neurofibroma, a histologically benign tumor of the peripheral nerve sheath that often involves adipose
J.M. Slopis (B)
Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
e-mail: jmslopis@mdanderson.org
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C Springer Science+Business Media, LLC 2011
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or connective tissues and vascular structures. Periorbital and orbital neurofibromas are histologically and developmentally distinct from optic pathway gliomas. Craniofacial neurofibromas may develop within the neural, muscular, and osseous elements of the orbital wall.
The “benign” nature of neurofibroma endows it with resistance to conventional chemotherapy and radiation therapy. Although optic pathway gliomas in NF1 patients are presumed to result from the same gene mutation, optic pathway gliomas may be more amenable to current treatment methods, which will be discussed later. Subsets of optic nerve gliomas do remain resistant to treatment, and more effective medical regimens are needed. Localization of the NF1 gene in 1970 and subsequent isolation of the neurofibromin protein in 1990 have led to the development of numerous strategies for treatment of NF1 using modulators of intracellular cell signal transduction, but novel treatment trials are just beginning.
The diagnosis of NF1 is based on clinical findings. The diagnostic criteria for NF1 (see Table 34.1) are based on a consensus statement by the National Institutes of Health, developed in 1988 [5] and reaffirmed in 1997 [6], representing the most frequent clinical features of NF1. The diagnosis of NF1 is established when two or more features from this list are identified in the patient.
Table 34.1 Diagnostic criteria for NF1
1.Six or more cafe-au-lait spots greater than 5 mm in diameter in prepubertal children or greater than 15 mm in diameter in postpubertal individuals
2.Two or more neurofibromas of any form or one plexiform neurofibroma
3.Freckling in the axillary or inguinal regions
4.Optic glioma
5.Two or more Lisch nodules (iris hamartomas)
6.Distinctive osseous lesion, such as sphenoid dysplasia or thinning of the long bone cortex with or without pseudoarthrosis
7.A first-degree relative with NF1 by the above criteria
Note: The presence of two or more criteria constitutes a definitive diagnosis in an individual. If an individual has a first-degree relative with NF1, then only one additional criterion is required for the diagnosis
The most promising development in genetic testing for NF1 is DNA sequencing of the NF1 coding region on chromosome 17. This technology has revealed great variability in DNA sequences in the NF1 gene region, as might be expected in a disorder with great clinical variability. Several hundred distinct mutation patterns, including deletions and rearrangements, have been found in DNA samples from individuals who meet clinical diagnostic criteria.
34.2 NF1 and the Optic Pathway
We will be restricting our discussion hereafter to NF1 and the visual sensory pathway. Optic pathway tumors occur in approximately 15% of patients with NF1 [7]. The overwhelming majority of these tumors are asymptomatic, and
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symptomatic tumors usually present in childhood. A small number of tumors become symptomatic in early adulthood. These tumors develop anywhere along the optic pathway, with each location presenting unique challenges in clinical management. Although most discussions of NF1 and the visual pathway refer to tumors as “optic gliomas,” several tumor types affect the visual pathways in NF1. We divide NF1-related tumors into four types related to their anatomic distribution: (1) periorbital and orbital neurofibroma, (2) intraorbital optic nerve glioma, (3) chiasmal and hypothalamic glioma, and (4) intraparenchymal astrocytoma.
Periorbital and orbital neurofibroma only rarely affects the orbital optic nerve; however, significant visual problems are created because of its amblyogenic potential (to be discussed below); therefore, we have included a discussion of this tumor in this chapter.
The NF1 gene plays a dominant role in fetal tissue development, and the impact may be general or focal in nature. The sequence of events in embryogenesis that leads to development of the brain and eyes includes interactions between developing bone, muscle, skin, neural tissue, and neural crest tissue. For this reason, in many cases the resulting tumors are actually dysplastic growths of multiple tissue (neurofibromata), and in the case of periorbital neurofibroma, these lesions can cause distortion of the normal periorbital anatomy. In cases of optic nerve gliomas, this may be an isolated finding among otherwise normal-appearing anatomic structures.
When necessary for cosmetic and/or vision problems, periorbital and orbital neurofibromas of NF1 are most often managed by surgical means alone. Optic nerve gliomas are usually managed conservatively, and there is controversy on how to manage these tumors when and if progressive visual loss ensues. Some continue conservative management without intervention; others use chemotherapy and, rarely, surgery depending on the specific anatomy. Radiation therapy may be considered for optic nerve gliomas when all other modalities fail and the patient is developing progressive visual loss; however, this modality may have significant morbidity in patients with NF1.
34.3 Periorbital and Orbital Neurofibroma
34.3.1 Description and Clinical Issues
Periorbital and orbital neurofibromas are relatively uncommon and are challenging tumors to manage. Most often these tumors form as plexiform neurofibromas and usually affect patients with NF1 within the first year of life [8]. Periorbital and orbital neurofibromas affect the face and are among the most disfiguring and problematic of all lesions in NF1 patients. Tissues involved include periorbital skin, fascia, and muscle, which are dysplastic tissues and often involve the eyelid and anterior part of the orbit. Rarely do these tumors affect the optic nerve, but they often affect vision because of several amblyogenic factors associated with the tumor (see below). The slow growth of plexiform neurofibromas often remains a persistent
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problem after surgical resection, especially in the case of tumors involving the eyelid that are not fully resected and continue to grow. Frequently, continued growth of a neurofibroma leads to progressive obstruction of the visual axis by simple overgrowth or by induction of ptosis due to levator muscle dysfunction. Surgical resection of the neurofibroma is often complicated because the dysplastic nature of the tumor obscures normal anatomic tissue planes and clean margins of resection cannot be obtained. Connective tissues often become excessively elastic over time because of the presence of the NF1 gene mutations, and slow regrowth of the tumor often leads to repeat surgical procedures throughout the patient’s lifetime. Bony dysplasia, particularly seen in the sphenoid bone, can lead to massive proptosis and brain herniation (Fig. 34.1).
Fig. 34.1 MRI findings in a patient with NF1 with severe sphenoid wing dysplasia and herniation of the brain parenchyma (the right temporal lobe) into the orbit causing massive proptosis. There is also a periorbital and subcutaneous neurofibroma that extends into the infratemporal and pterygopalatine fossa. Figure courtesy of Dr. Bita Esmaeli
It is very rare for a plexiform neurofibroma of the eyelid or orbit to affect the ipsilateral optic nerve. Additionally, it is unusual for a child with a plexiform neurofibroma of the eyelid or orbit to have a concomitant optic nerve glioma in the same eye, but this scenario is sometimes encountered and makes identifying the cause of progressive visual loss more difficult.
34.3.2 Evaluation and Management
Preoperative assessment includes magnetic resonance imaging (MRI) of the face and orbit to determine the extent of the tumor in the periorbita and orbit. T1and T2-weighted MRI sequences are helpful in delineating the margins of tumor amid distorted anatomic structures. Contrast enhancement offers little useful information, but special imaging sequences, including fat-suppressed MRI, may
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be helpful. Three-dimensional computed tomography (CT) with reconstruction is often useful in defining associated features resulting from NF1, such as bony dysplasia of the orbit and associated facial structures, when this information is required.
Routine ophthalmologic examination is mandatory. Periorbital and orbital neurofibromas can cause amblyopia due to one or more of the following three mechanisms: (1) Occlusion amblyopia caused by the lid covering the visual axis. (2) Anisometropic amblyopia caused by a ptotic, heavy lid creating a pressure-induced astigmatism in the affected eye. If this refractive error is left uncorrected, it leads to refractive amblyopia. This can happen without the visual axis being covered, leading to a false belief that amblyopia is not present because the visual axis is uncovered.
(3) Strabismic amblyopia caused by an ocular muscle imbalance that often is not obvious and requires ophthalmic skill to detect. This problem can happen silently and may be missed if the patient is not properly examined. As stated before, plexiform neurofibromas do not usually involve the orbit to the extent that they cause optic neuropathy, but this is still a potential source of decreased vision.
Different from the periorbital and orbital plexiform neurofibroma described above, occasionally isolated orbital neurofibromas can develop that may cause proptosis or strabismus (with or without visual loss depending on its bulk) and may have amblyogenic potential and less likely compress the optic nerve. These tumors arise from nerves within the orbit and may involve the superior orbit, including the lacrimal gland, or the inferior orbit.
Periorbital and orbital neurofibromas include cutaneous and subcutaneous elements that can undergo malignant transformation; however, concern about malignant transformation is not the basis for considering intervention [9].
The risk of malignant transformation is about 7–10% for neurofibromas in patients with NF1, and transformation of an orbital neurofibroma to a soft tissue sarcoma may also be encountered [10].
It is therefore important to have an ophthalmologist experienced in amblyopia detection and management routinely evaluate those with periorbital and orbital neurofibromas to maintain the best possible vision by management of amblyopia. Additionally, plexiform neurofibromas in NF1 patients are sometimes associated with congenital glaucoma, and this needs to be examined for carefully by a trained ophthalmologist. There is up to a 50% chance of glaucoma on the side of the neurofibroma, and this glaucoma may present as buphthalmos with or without corneal edema. The risk of glaucoma is higher in patients with NF1 with ectropion uvea. Of course malignant degeneration needs to be looked for with a rapid growth phase.
Indications for surgical intervention vary from case to case. Apparent progression toward occlusive ptosis and facial disfigurement should be the primary indications for intervention. There is no specific age required for surgical intervention; however, surgery is usually delayed as long as possible because of the recurrent nature of these tumors. There is no predictable growth pattern of periorbital and orbital tumors, although some may progress more rapidly when children enter puberty and therefore this may not indicate malignant transformation.