From Emory Eye Center, Emory University School of Medicine, Atlanta, Georgia.
Supported in part by an unrestricted department grant from Research to Prevent Blindness, Inc., New York, New York.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Hans E. Grossniklaus, MD, MBA, L. F. Montgomery Ophthalmic Pathology Laboratory, BT428, 1365B Clifton Road, Atlanta, GA 30322.
Tuberous sclerosis was first described in 1880 by the French neurologist Désiré-Magloire Bourneville when he described the brain lesions found postmortem in a 15 year old who had suffered seizures since infancy.1 Tuberous sclerosis is a congenital neurocutaneous syndrome characterized by widespread hamartomas in the skin, brain, eye, and visceral organs. In 1998, the National Institutes of Health standardized the diagnostic criteria for tuberous sclerosis complex.2,3 The retinal tumors associated with tuberous sclerosis complex consist mostly of astrocytes, but a few cases of larger tumors, so-called giant cell astrocytomas, with more aggressive behavior have been described in patients with tuberous sclerosis complex with ages ranging from 1 to 14 years. We describe a 1-month-old male infant with a giant cell astrocytoma of the retina that did not reveal any calcification or necroses that have been associated in all previously described cases.
A 1-month-old twin male infant with a previous history of tuberous sclerosis was evaluated for leukocoria. On fundus examination, he was found to have a large left intraocular tumor. The prenatal and family histories were noncontributory. Physical examination revealed several flat, hypopigmented skin lesions ranging from 1 to 2 cm consistent with Ash leaf spots on his trunk and lower extremities.
Ophthalmic examination revealed normal anterior segments and a large white tumor involving the macula and temporal half of the fundus in the left eye with associated subretinal fluid (Fig. 1A). The mass measured 7.8 mm in height and 11.8 × 11.0 mm in basal diameter. It was located 2 mm temporal to the optic nerve. The central retinal artery and vein were dilated and the disc was engorged. No seeding was identified. The mass appeared exophytic with associated subretinal fluid and retinal detachments.
Figure 1. (A) The Left Eye Contains a Large Tumor Temporal to the Optic Nerve. There Is Associated Subretinal Fluid. (B) B-Scan Ultrasonography of the Left Eye Discloses a Solid Intraocular Tumor (7.8 × 11.8 × 11 mm) Without Calcospherites.
The intraocular pressure was within normal limits. B-scan ultrasonography showed a left intraocular tumor with no calcification (Fig. 1B). The differential diagnoses of leukocoria in the presence of a large unilateral retinal mass included retinoblastoma and retinal astrocytoma given the child’s known diagnosis of tuberous sclerosis complex. The right fundus was normal. Magnetic resonance imaging and computed tomography showed multiple subependymal and subcortical white matter lesions consistent with tuberous sclerosis. Given the size of the mass, poor visual prognosis, and a small possibility of a retinoblastoma, enucleation of the left eye was performed.
A 10 × 9 mm white tumor was present 2 mm temporal to the optic nerve head (Fig. 2A). Microscopic examination showed a temporal exophytic tumor arising in the macula. The tumor was composed of giant, round cells with abundant, glassy, eosinophilic cytoplasm, displaced nuclei, and prominent nucleoli (Fig. 2B). It also contained spindle-shaped cells with fusiform nuclei and prominent nucleoli (Fig. 2C). There were no mitotic figures noted. The tumor contained vascular channels and scattered aggregates of mononuclear inflammatory cells. There were no areas of necrosis or calcospherites. A separate 0.5 × 0.5 mm focal proliferation of spindle-shaped cells was present in the nerve fiber layer of the nasal retina. The central retinal artery and vein were dilated.
Figure 2. (A) A Large White Mass Is Present Temporal to the Optic Nerve. (B) The Mass Is Composed of Giant Round Cells with Displaced Nuclei and Prominent Nucleoli (hematoxylin–Eosin, Original Magnification ×100). (C) Spindle-Shaped Cells with Fusiform Nuclei and Prominent Nucleoli Are also Present (hematoxylin–Eosin, Original Magnification ×100). (D) The Spindle-Shaped Cells Stained Positively for Neuron-Specific Enolase (original Magnification ×100). (E) The Giant Cells Stained Positively for Glial Fibrillary Acidic Protein (original Magnification ×100).
Immunohistochemical stains were positive for neuron-specific enolase, glial fibrillary acidic protein, and S-100 protein in both cell types (Figs. 2D and 2E). CD3 and CD68 staining were positive in the mononuclear inflammatory cells. Ultrastructurally, the giant tumor cells demonstrated abundant smooth and rough endoplasmic reticulum, whereas spindle-shaped tumor cells revealed collections of complex interdigitations on electron microscopy (Fig. 3). The diagnosis was giant cell astrocytoma of the retina.
Figure 3. Electron Micrograph. (A and B) the Giant Tumor Cell Displays Abundant Profiles of Intracytoplasmic Rough Endoplasmic Reticulum (original Magnification ×1,900 and ×7,200, Respectively). (C and D) Spindle-Shaped Tumor Cells Show Interdigitations and Intracellular Intermediate Filaments (original Magnification ×2,900 and ×1,9000, Respectively).
Tuberous sclerosis complex is caused by loss of function in one of two genes: TSC1, located on human chromosome 9q34, or TSC2, located on 16p13. The proteins encoded by TSC1 and TSC2 are called “hamartin” and “tuberin,” respectively. Close phenotypic similarities between the features associated with TSC1 and TSC2 mutations suggest that tuberous sclerosis complex is a disease characterized by locus heterogeneity.4–6 Hamartin and tuberin, the cellular proteins encoded by TSC1 and TSC2, are now known to interact to suppress the P13K signal transduction pathway. They integrate two important signals governing cell growth: growth factors and nutrients.1
The benign brain hamartomas that occur in tuberous sclerosis complex include: (1) cortical tubers, consisting of fascicles of neurons, astrocytes, and giant cells; (2) subependymal nodule, which resembles cortical tuber but has a higher cellular packing density; and (3) subependymal giant cell astrocytoma, which contains cells with more prominent nuclei and abundant, glassy, eosinophilic cytoplasm. Immunohistochemical and ultrastructural studies have indicated that these giant cells arise from mixed glioneuronal precursors.
One of the most worrisome differential diagnoses of leukocoria in children that often leads to enucleation is retinoblastoma, the most common intraocular malignancy in children. Patients usually present with leukocoria or strabismus. Rosettes such as Homer–Wright or Flexner–Wintersteiner rosettes can be found in retinoblastomas. In contrast, astrocytic hamartomas of the retina that are commonly found in tuberous sclerosis complex have a limited invasive potential. Giant cell retinal astrocytomas are considered to have more aggressive features such as secondary retinal detachment and neovascular glaucoma.7
As described in the article by Shields et al.,7 the clinicopathologic features of retinal astrocytomas include a sessile or slightly elevated lesion that may be unilateral, bilateral, solitary, multifocal, transparent, opaque, noncalcified, or calcified.8,9 In their study of four enucleated eyes from patients with tuberous sclerosis complex and aggressive retinal giant cell atrocytoma,7 the patients’ ages ranged from 1 to 14 years. One eye had a solitary tumor and three had multiple tumors, with the large, aggressive tumors located posteriorly and the smaller, nonprogressive tumors located anteriorly, similar to the current case. The aggressive tumors exhibited 50% to 95% necrosis and all contained calcospherites.7 All eyes exhibited neovascularization of the iris.7
Interestingly, the tumor in the current case did not contain calcospherites, although there were foci of CD3+ and CD68+ inflammatory cells present. These represent T cells and macrophages, respectively. The age of the current patient was 1 month, and it is possible that the inflammatory infiltrates are precursors of areas of necrosis where dystrophic calcification in the form of calcospherites will eventually form. Additionally, neovascularization of the iris may have eventually developed in the current case. Therefore, the pathologic findings in the current case are consistent with early findings in aggressive retinal giant cell astroctyoma in a patient with tuberous sclerosis complex. Unlike the findings of Shields et al.,7 the giant cells in the current case immunostained for both neuronal (neuron-specific enolase and S-100 protein) and glial (glial fibrillary acidic protein) markers, consistent with a neuronal or glial precursor cell of origin. There were also no hamartomas of the iris or ciliary body in the current case, as previously described.10
There have been eight reported cases of eyes enucleated with enlarging retinal astrocytomas in patients with evidence of tuberous sclerosis complex.7,11 All except one of these patients were 14 years or younger at the time of enucleation. The one exception was a 27-year-old woman.11 Critical review of that case shows that the retinal tumor did not have the aggressive histopathologic features outlined by Shields et al.,7 thus leading to the speculation that the patient had a form furste or more benign clinical variant than patients with aggressive giant cell astroctyomas.7 Conversely, there have been 12 reports describing the pathologic findings in patients without apparent tuberous sclerosis complex whose eyes were enucleated for enlarging retinal astrocytomas.7,12 Five of the cases occurred in children 9 years or younger, including two in children 1 year or younger.12,13 It is possible that tuberous sclerosis complex was diagnosed at a later age in these young patients.
- McCall T, Chin SS, Salzman KL, Fults DW. Tuberous sclerosis: a syndrome of incomplete tumor suppression. Neurosurg Focus. 2006;20:E3. doi:10.3171/foc.2006.20.1.4 [CrossRef]
- Hyman MH, Whittemore VH. National Institutes of Health consensus conference: tuberous sclerosis complex. Arch Neurol. 2000;57:662–665. doi:10.1001/archneur.57.5.662 [CrossRef]
- Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference; revised clinical diagnostic criteria. J Child Neurol. 1998;13:624–628. doi:10.1177/088307389801301206 [CrossRef]
- Povey S, Burley MW, Attwood J, et al. Two loci for tuberous sclerosis: one on 9q34 and one on 16p13. Ann Hum Genet. 1994;58:107–127. doi:10.1111/j.1469-1809.1994.tb01881.x [CrossRef]
- Niida Y, Lawrence-Smith N, Banwell A, et al. Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis. Hum Mutat. 2000;14:412–422. doi:10.1002/(SICI)1098-1004(199911)14:5<412::AID-HUMU7>3.0.CO;2-K [CrossRef]
- van Slegtenhorst M, Verhoef S, Tempelaars A, et al. Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation. J Med Genet. 1999;36:285–289.
- Shields JA, Eagle RC Jr, Shields CL, Marr BP. Aggressive retinal astrocytomas in 4 patients with tuberous sclerosis complex. Arch Ophthalmol. 2005;123:856–863. doi:10.1001/archopht.123.6.856 [CrossRef]
- Shields JA, Shields CL. Glial tumors of the retina and optic disc. In: Shields JA, Shields CL. Intraocular Tumors: A Text and Atlas. Philadelphia: W. B. Saunders; 1992:422–431.
- Shields JA, Shields CL. Glial tumors of the retina and optic disc. In: Shields JA, Shields CL. Atlas of Intraocular Tumors. Philadelphia: Lippincott, Williams and Wilkins; 1999:272–283.
- Eagle RC Jr, Shields JA, Shields CL, Wood MG. Hamartomas of the iris and ciliary epithelium in tuberous sclerosis-complex. Arch Ophthalmol. 2000;118:711–715.
- Margo CE, Barletta JP, Staman JA. Giant cell astrocytoma of the retina in tuberous sclerosis. Retina. 1993;13:155–159. doi:10.1097/00006982-199313020-00013 [CrossRef]
- Jakobiec FA, Brodie SE, Haik B, Iwamoto T. Giant cell astroctyoma of the retina: a tumor of possible Mueller cell origin. Ophthalmology. 1983;90:1565–1576.
- Ulbright TM, Fulling KH, Helveston EM. Astrocytic tumors of the retina: differentiation of sporadic tumors from phakomatosis-associated tumors. Arch Pathol Lab Med. 1984;108:160–163.