A, A 6-year-old boy had been born with a left facial deformity that eventually developed into an extensive plexiform neurofibroma. B, At age 1 year, magnetic resonance imaging disclosed an enlarged, left buphthalmic eye globe (arrowhead) from glaucoma, a thin optic nerve (N), and an anterior cranial fossa arachnoid cyst (AC). C, By age 6 years, the left globe had become pthisical and disorganized. There is an intravitreal mass (A), choroidal thickening (B), and osseous metaplasia of the pigment epithelium (C). AC indicates stable arachnoid cyst. D, The enucleated globe with the cornea (CO) on the left displays a fibrous membrane (black arrowhead) on the surface of an atrophic iris. A solid tumor (T) has filled a contracted vitreous cavity. Osseous metaplasia of the retinal pigment epithelium (yellow arrowhead), striking choroidal thickening (CH), thickening of the sclera due to globe shrinkage, and enlarged but nonneuromatous short posterior ciliary nerves (CN) are also present (hematoxylin-eosin, original magnification ×12.5).
A, Small nerve branches or Schwann cell clusters (arrowheads) are observed in the choroid. They are typically not seen in normal eyes. S indicates sclera (hematoxylin-eosin, original magnification ×100). B, A cyst within the tumor (T) contains cholesterol clefts (CC). There is thickening including prominent melanocytes of the adjacent choroid (CH). S indicates sclera (hematoxylin-eosin, original magnification ×40). C, Eosinophilic spindle cells with widely separated, small, regular nuclei and perivascular collections of migrated pigment epithelial cells (arrowheads) are seen (hematoxylin-eosin, original magnification ×100). D, Intravitreal tumor (T) uniformly and intensely immunostains for the presence of glial fibrillary acidic protein. Small and large cysts (C) are distributed throughout the tumor (immunoperoxidase reaction, diaminobenzidine chromogen, hematoxylin counterstain, original magnification ×40). Inset, Higher-magnification image shows glial fibrillary acidic protein–positive, elongated fibrous astrocytes composing the massive retinal gliosis (immunoperoxidase reaction, diaminobenzidine chromogen, hematoxylin counterstain, original magnification ×200).
Jakobiec FA, Rashid A, Lewis K. Massive Retinal Gliosis in Neurofibromatosis Type 1. JAMA Ophthalmol. 2015;133(1):100-102. doi:10.1001/jamaophthalmol.2014.3958
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Neurofibromatosis type 1 (NF1), an autosomal dominant syndrome, has major extraocular expressions of bilateral ptosis, diffuse and plexiform neurofibromas, optic nerve gliomas, and dysplasia of the sphenoid bone. With respect to the eyeball, the spectrum of involvement includes enlarged corneal nerves, Lisch iris nodules, dysplasia of the anterior chamber angle causing glaucoma, multiple choroidal nevi (formerly called fundus café au lait spots), diffuse uveal hamartomatous thickening (containing a mixture of melanocytes, Schwann cells, and occasional ganglion cells), enlarged nerves, uveal peripheral nerve tumors, and rare retinal astrocytic hamartomas.1,2 In this article, we describe the first association, to our knowledge, between massive retinal gliosis (MRG) and NF1.3,4
A 6-year-old boy had left upper eyelid ectropion, floppy eyelid syndrome, and neurofibromatosis (Figure 1A). Both his mother and maternal grandmother had NF1. In his first year of life he developed glaucoma, a vitreous hemorrhage of unknown cause, and epilepsy. Magnetic resonance imaging (Figure 1B) revealed buphthalmos, left cerebral hemispheric atrophy, an arachnoid cyst, leptomeningeal enhancement with calcifications consistent with Sturge-Weber syndrome, and a large left facial and orbital plexiform neurofibroma. The right eye was normal. The left eye slowly became phthisical. Repeated magnetic resonance imaging (Figure 1C) demonstrated a shrunken globe, a vitreous mass, and left optic nerve atrophy. An enucleation was performed because of ocular pain.
The enucleated left eyeball (Figure 1D) measured 21 × 16 × 17 mm and had enlarged posterior ciliary nerves. Histopathological examination revealed angle closure, a fibrous membrane on the iris surface, and a mass filling the vitreous cavity. There was osseous metaplasia of the retinal pigment epithelium and a small lens remnant had undergone complete fibrous metaplasia. The uvea displayed diffuse hamartomatous thickening (Figure 2A) and enlarged short posterior ciliary nerves (Figure 1D). The vitreous mass exhibited scattered cysts with cholesterol clefts (Figure 2B) and had destroyed the retina. The mass was composed of eosinophilic spindle cells with perivascular pigment deposition (Figure 2C). It did not involve the optic nerve. Glial fibrillary acidic protein and S-100 protein intensely immunostained the vitreous mass (Figure 2D). Neurofilament, synaptophysin, p53, and Ki-67 were all negative.
Astrocytic retinal lesions are exceptional in NF1.1 Six vasoproliferative tumors of the retina in NF15 (reactive combination lesions of astrocytes and capillaries6) have been described and could serve as a precursor of MRG in some instances.3,6 Massive retinal gliosis is typically a reactive, nonneoplastic, unilateral condition (bilaterality has been reported in 3 cases3) that develops in adults (32 of 38 patients were adults in the largest series4). The hallmark of MRG is a proliferation of fibrillated eosinophilic spindle cells that replace the vitreous cavity. Strong glial fibrillary acidic protein positivity confirms the diagnosis. Thickening of the vessel walls, perivascular pigment, intralesional cysts, and calcareous deposits (calcospherites) are also detectable.
Massive retinal gliosis is characteristically encountered in phthisical eyes after trauma, surgery, or inflammation and in other conditions such as retinopathy of prematurity or Coats disease.3 Our patient’s MRG was probably a poorly modulated reparative response to an unexplained preceding hemorrhage in the eye. The smaller retinal vasoproliferative tumors are also seen in such settings, implying that they too are usually reactive.5,6 We doubt there is any intrinsic retinal property in NF1 that is conducive to MRG. Studies of MRG have preliminarily shown polyclonality, further supporting a reactive lesion.3 Immunostains for p53 and Ki-67 here are close to negative, whereas they are positive (>10% of cells) in astrocytic neoplasms.6 Retinoblastomas can be distinguished from MRG with imaging studies by virtue of the former’s more prominent calcifications, from medulloepitheliomas that have ciliary region cysts, and from pediatric melanomas, which preferentially arise in the anterior segment of the eye.
Corresponding Author: Frederick A. Jakobiec, MD, DSc, David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114 (firstname.lastname@example.org).
Published Online: October 9, 2014. doi:10.1001/jamaophthalmol.2014.3958.
Author Contributions: Drs Jakobiec and Rashid had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Jakobiec, Rashid.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Jakobiec, Rashid.
Critical revision of the manuscript for important intellectual content: All authors.
Administrative, technical, or material support: All authors.
Study supervision: All authors.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.