Retinal Glioneuronal Hamartoma in Neurofibromatosis Type 1

LETTERS

age 20 months, the right eye was enucleated owing to it RESEARCH LETTERS being blind and painful with a fixed pupil and corneal haze. Postoperatively, she was more comfortable, no lon- ger photophobic, and without tearing. Retinal Glioneuronal Hamartoma Gross pathologic examination revealed a buphthal- mic eye with a Baerveldt glaucoma drainage implant on in Neurofibromatosis Type 1 the superonasal sclera. On oblique sectioning, the cor- etinal tumors occasionally arise in patients with nea was clear but thinned. The anterior chamber was filled neurofibromatosis type 1 (NF1). There have been with a tan, milky fluid. The pupil was widely dilated and reports of astrocytic hamartomas, capillary hem- the iridocorneal angle was closed by peripheral anterior R synechiae. The lens and uveal tract were unremarkable. angiomas, and combined hamartomas of the retina and retinal pigment epithelium (CHRRPE)—typically with- There was a funnel-shaped retinal detachment. out pathologic confirmation of the diagnosis.1,2 We re- Microscopic examination revealed an absent Bow- port a case of a child with NF1 with an unusual retinal man layer, which was replaced by an area of thin cellu- tumor, a glioneuronal hamartoma. lar fibrosis. A membrane composed of corneal endothe- lial cells was present over the surface of the severely Report of a Case. Our patient was born at term with buph- contracted iris and ciliary body. The lens showed cata- thalmos and proptosis of her right eye, accompanied by ract formation with anterior calcific degeneration and pos- corneal clouding and increased tearing. She was subse- terior migration of the lens epithelium. quently noted to have right sphenoid wing dysplasia, mul- The uvea was thickened by a diffuse neurofibroma typi- tiple cutaneous plexiform neuromas of the right eyelids cal for eyes involved with NF1. The predominant spindle and face (fifth nerve distribution), right hemispheric dys- cells within the neurofibroma reacted positively with S-100 plastic polymicrogyria, and a seizure disorder. She was protein and microtubule-associated protein 2 but were diagnosed as having NF1. The left eye was within nor- negative for glial fibrillary acidic protein, CD56 (neural mal limits. The patient received a Baerveldt glaucoma cell adhesion molecule—a marker of neurons, astro- drainage implant at age 5.5 months. At age 8 months, a cytes, and nonmyelinating Schwann cells), neurofila- dilated fundus examination revealed temporal retinal whit- ment, and Ki-67. Scattered clusters of larger neuronal cells ening and posterior retinal hemorrhages, which were ini- with comparatively more abundant cytoplasm and large tially attributed to a retinal vein occlusion. Four months round nuclei with prominent nucleoli were also present later, the patient was diagnosed clinically as having a and were positive for synaptophysin, microtubule- CHRRPE (Figure 1). Enlargement of the retinal tumor associated protein 2, and neurofilament (Figure 2). was noted over the following 8 months, accompanied by The detached retina was displaced anteriorly and cen- the development of a vitreous hemorrhage, tractional reti- trally by a fibrovascular proliferation in the vitreous. A nal detachment, and proliferative vitreoretinopathy. At retinal tumor replaced a broad area of the inner retina

A B

Figure 1. Right eye of the patient. A, Fundus photograph of the right eye (Retcam, 130° view; Clarity Medical Systems) demonstrates a hamartomatous lesion inducing tractional retinal detachment along the inferotemporal arcade with concurrent inferotemporal branch retinal vein occlusion and preretinal hemorrhage. B, Whole eye with diffusely thickened uvea and complete retinal detachment.

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Figure 2. Histologic findings in the right eye. A, Whole eye with detached retina, large retinal cyst (asterisk), and severely contracted iris with peripheral anterior synechiae (arrows) (hematoxylin-eosin, original magnification ϫ15). B, Retina (hematoxylin-eosin, original magnification ϫ40). C, Retinal tumor (hematoxylin-eosin, original magnification ϫ400). D, Retinal tumor, showing the retinal surface (black arrow) and neuronal cells beneath the inner nuclear layer (white arrows) (hematoxylin-eosin, original magnification ϫ400). E, Retinal tumor (glial fibrillary acidic protein, original magnification ϫ400). F, Retinal tumor (CD56, original magnification ϫ400). G, Choroid with neurofibroma, including clusters of neurons (hematoxylin-eosin, original magnification ϫ400); inset, neurons with round nuclei and cytoplasmic Nissl substance (hematoxylin-eosin, original magnification ϫ600). H, Choroid (microtubule-associated protein 2, original magnification ϫ400).

in a diffuse but irregular manner, focally extending into a neoplasm such as ganglioneuroma. Aggressive retinal as- the vitreous. The outer retinal layers were compara- trocytomas have been described in patients with tuber- tively preserved. Scattered larger neuronal cells resem- ous sclerosis complex. These tumors also stain positive for bling those seen in the choroid were also present. both neuronal and glial markers. Unlike our case, these The abnormal spindle cells within the retina were im- astrocytomas occur in a juxtapapillary location and con- munoreactive for S-100 protein, glial fibrillary acidic pro- tain broad areas of necrosis. Where our patient has mor- tein, and CD56. The larger neuronal cells were positive phologically recognizable ganglion cells, these tuberous for both synaptophysin and microtubule-associated pro- sclerosis complex–related astrocytomas contain atypical tein 2, providing evidence of neuronal differentiation. cells resembling those seen in cortical tubers and subep- These cells were fewer in number than in the choroid. endymal giant cell astrocytoma.3 Glioneuromas com- Where the retinal architecture was relatively preserved, posed of admixed glial and neuronal cells have also been neuronal cells were seen subjacent to the inner nuclear reported in patients without a diagnosis of NF1.4,5 layer. Scattered intact axons were identified in the nerve To our knowledge, this is the first report of a retinal fiber layer on a neurofilament immunohistochemical stain. glioneuronal hamartoma in NF1. While ocular findings No mitotic figures were identified, and a Ki-67 stain such as iris Lisch nodules, ciliary body and diffuse cho- showed no proliferative activity. roidal neurofibromas, optic nerve gliomas, sphenoid bone The retinal pigment epithelium was unremarkable ex- dysplasia, and eyelid plexiform neuromas have fre- cept for the presence of drusen. No retinal pigment epi- quently been noted in patients with NF1,6-8 retinal tu- thelial cells were seen in the retina. There was no CHRRPE. mors have rarely been described. Many retinal tumors have been reported in association with NF1, but most Comment. Clinical diagnosis of retinal tumors may be without pathologic descriptions.9-11 There are few re- inaccurate, as pathologic evaluation may result in a dif- ports detailing the histopathologic findings of large as- ferent diagnosis. Initially, the dilated fundus examina- trocytic hamartomas.3,12-14 Patients with NF1 can also show tion revealed posterior hemorrhages and temporal reti- diffuse hyperplasia or benign neoplasia of the connec- nal whitening similar in clinical appearance to a retinal tive tissue, meningeal, and glial elements in the central vein occlusion. Four months later, the patient was diag- or peripheral nervous system.15 nosed clinically as having a CHRRPE. As the tumor en- In conclusion, our case is best classified as a glioneu- larged and penetrated the internal limiting membrane, ronal hamartoma and suggests that the CHRRPE may it expanded into the vitreous, resulting in retinal detach- be an incorrect clinical diagnosis in the absence of ment. Histopathologic analysis of the lesion showed a pro- pathologic analysis. Absent proliferative activity argues liferation of spindle cells with scattered admixed neu- for a hamartomatous etiology over a neoplasm such as a rons. The histogenetic origin of the spindle cells cannot ganglioneuroma. be identified with certainty, but the morphology along with the coexpression of CD56 and S-100 protein in the retina suggest nonmyelinating Schwann cells. Eleonora M. Lad, MD, PhD The nomenclature in this case is difficult. We favor the Jason R. Karamchandani, MD term glioneuronal hamartoma given that the tumor was com- Deborah M. Alcorn, MD posed of both glial and neuronal cells. The lack of prolif- Darius M. Moshfeghi, MD erative activity argues for a hamartomatous etiology over Peter R. Egbert, MD

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Author Affiliations: Department of Ophthalmology, Duke tropia and amblyopia in the left eye was noted to have a University, Durham, North Carolina (Dr Lad); Depart- depigmented macular lesion in her left eye. The patient ment of Laboratory Medicine and Pathobiology, Univer- was undergoing patching therapy for amblyopia and sity of Toronto, Toronto, Ontario, Canada (Dr Karam- was otherwise healthy. Family history was significant chandani); and Department of Pediatrics, Lucile Packard for neurofibromatosis affecting her father and paternal Children’s Hospital at Stanford (Dr Alcorn) and Eye In- grandmother, the latter of whom had neoplasms of the stitute at Stanford, Stanford University School of Medi- brain, eyes, and auditory nerves that led to deafness, cine (Drs Alcorn, Moshfeghi, and Egbert), Stanford, blindness, and death by age 34 years. On genetic test- California. ing, the child and her father were confirmed to have de- Correspondence: Dr Egbert, Eye Institute at Stanford, letion of the NF2 promoter and exon 1, described as 2452 Watson Ct, MC 5353, Palo Alto, CA 94303 (egbert c.-854-?_45-?del. @stanford.edu). Visual acuity was central, steady, and maintained in Author Contributions: Drs Lad and Karamchandani con- the right eye and central, steady, and unmaintained in tributed equally to this work. the left eye. There was no afferent pupillary defect. Ocu- Financial Disclosure: None reported. lar versions were full with a left esotropia of 30 to 40 prism diopters. Cycloplegic refraction was ϩ3.00 sphere OD 1. Tsai P, O’Brien JM. Combined hamartoma of the retina and retinal pigment ϩ epithelium as the presenting sign of neurofibromatosis-1. Ophthalmic Surg and 2.00 sphere OS. Slitlamp examination showed nor- Lasers. 2000;31(2):145-147. mal anterior segments without cataracts or Lisch iris nod- 2. Destro M, D’Amico DJ, Gragoudas ES, et al. Retinal manifestations of neu- ules. Fundus examination of the left eye revealed a gray, rofibromatosis: diagnosis and management. Arch Ophthalmol. 1991;109 ϫ (5):662-666. flat, macular lesion occupying an area of 2 2.5 disc di- 3. Shields JA, Eagle RC Jr, Shields CL, Marr BP. Aggressive retinal astrocyto- ameters, partially obscuring underlying retinal and peri- mas in 4 patients with tuberous sclerosis complex. Arch Ophthalmol. 2005; Figure 1 123(6):856-863. foveal vasculature ( A). A clinical diagnosis of 4. Addison DJ, Font RL. Glioneuroma of iris and ciliary body. Arch Ophthalmol. a dense macular ERM in the left eye, possibly hamarto- 1984;102(3):419-421. matous in etiology and possibly visually significant, was 5. Kivela¨ T, Kauniskangas L, Miettinen P, Tarkkanen A. Glioneuroma associated with colobomatous dysplasia of the anterior uvea and retina: a case simu- made. A small gray inner retinal opacity was also noted lating medulloepithelioma. Ophthalmology. 1989;96(12):1799-1808. in the perifoveal region of the right eye (not shown). Mag- 6. Lewis RA, Riccardi VM. Von Recklinghausen neurofibromatosis: incidence netic resonance imaging of the brain and spine revealed of iris hamartomata. Ophthalmology. 1981;88(4):348-354. 7. Huson S, Jones D, Beck L. Ophthalmic manifestations of neurofibromatosis. no tumors. Br J Ophthalmol. 1987;71(3):235-238. Examination under anesthesia was performed. 8. Woog JJ, Albert DM, Solt LC, Hu DN, Wang WJ. Neurofibromatosis of the eyelid and orbit. Int Ophthalmol Clin. 1982;22(3):157-187. Spectral-domain optical coherence tomography (Biopti- 9. Frenkel M. Retinal angiomatosis in a patient with neurofibromatosis. Am gen, Inc) of the left eye demonstrated a thickened ERM J Ophthalmol. 1967;63(4):804-808. and underlying neurosensory retina with evidence of 10. Landau K, Dossetor FM, Hoyt WF, Muci-Mendoza R. Retinal hamartoma in neurofibromatosis 2. Arch Ophthalmol. 1990;108(3):328-329. vitreous attachment to the membrane that caused slight 11. Vianna RN, Pacheco DF, Vasconcelos MM, de Laey JJ. Combined hamar- elevation at its edges (video, http://www.archophthalmol toma of the retina and retinal pigment epithelium associated with neurofi- .com). Fluorescein angiography showed apparent ab- bromatosis type-1. Int Ophthalmol. 2001;24(2):63-66. 12. Ulbright TM, Fulling KH, Helveston EM. Astrocytic tumors of the retina: sence of a foveal avascular zone due to perifoveal hyper- differentiation of sporadic tumors from phakomatosis-associated tumors. Arch vascularity that crossed the horizontal raphe centrally Pathol Lab Med. 1984;108(2):160-163. 13. Martyn LJ, Knox DL. Glial hamartoma of the retina in generalized neurofi- (Figure 1B). The macular ERM showed no intrinsic vas- bromatosis, Von Recklinghausen’s disease. Br J Ophthalmol. 1972;56(6): cularity. The patient underwent pars plana vitrectomy 487-491. and ERM stripping in the left eye. The membrane was 14. Gass JD. An unusual hamartoma of the pigment epithelium and retina simu- lating choroidal melanoma and retinoblastoma. Trans Am Ophthalmol Soc. 1973;71:171-185. 15. Shields JA, Shields CL. Intraocular Tumors: An Atlas and Textbook. 2nd ed. Video available online at Philadelphia, PA: Lippincott Williams & Wilkins; 2008. www.archophthalmol.com noted to be densely adherent to the macula but with a definite anatomic plane between the membrane and retina. Surgical Removal of an Atypical Macular As the membrane separated, so did a continuous poste- Epiretinal Membrane in Neurofibromatosis rior vitreous membrane, presumably a layer of the pos- Type 2: Clinicopathologic Correlation terior cortical vitreous. The membrane was submitted for and Visual Outcome histologic studies. Light microscopy showed a highly cel- lular membrane with up to 4 layers of cells in some areas. acular epiretinal membranes (ERMs) are com- There was weak staining for glial fibrillary acidic protein mon manifestations in children with neuro- (Figure 2). There was insufficient specimen for ad- M fibromatosis type 2 (NF2).1 The ERMs in NF2 equate evaluation of periodic acid–Schiff or S-100 pro- have been speculated to be hamartomatous in nature. Im- tein staining. The cells were of indeterminate origin; no munohistological techniques have rarely been used to astrocytes were identified in the limited amount of tissue characterize these ERMs.2 The following case describes available. Visual acuity was 20/20 OD and 20/125 OS 6 the clinical and histologic characteristics of a dense ERM months after vitrectomy and continued refractive and am- in a case of NF2. blyopia management that consisted of part-time occlusion of the right eye. The retinal vasculature in the left Report of a Case. During a dilated fundus examination, macula remained unchanged in appearance without re- a 2-year-old girl with confirmed NF2 and a history of eso- currence of ERM.

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