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Arch Ophthalmol. 2004;122:390-393.

Leukocoria caused by diverse ocular conditions is distinguishable by history, characteristic clinical findings, and ancillary imaging. Atypical cases pose a diagnostic dilemma necessitating enucleation if retinoblastoma or malignancy cannot be excluded. We report a newborn with leukocoria in a microphthalmic eye containing an uncalcified subretinal mass. Teratoid medulloepithelioma was suspected. Instead, benign heterotopic brain tissue was found, which to our knowledge has only been reported once before,¹ due to aberrant differentiation of the neurectoderm into cerebral gray matter instead of the retina.

Report of a Case
A 5-day-old, healthy baby girl with leukocoria of the microphthalmic right eye was seen in the Retinoblastoma Program at the Hospital for Sick Children, Toronto, Ontario. Perinatal and family histories were unremarkable. The left eye was normal, but the right eye appeared blind. Under general anesthesia, intraocular pressure and ocular movements were normal. The 8-mm-diameter right cornea was clear and the anterior chamber, deep. The iris was hypoplastic with persistent tunica vasculosa lentis bridging the pupil. The irregularly shaped lens was small but clear. Zonules were incomplete (Figure 1). A large, nasal, creamy-white, elevated subretinal mass, obscuring the retina and optic nerve, extended into the clear vitreous until just behind the lens.

View larger version (63K): [in this window] [in a new window] Figure 1. Digital camera results show a clear cornea; prominent, immature iris vasculature; a small, irregularly shaped lens; absent zonules except inferonasally; and leukocoria due to a large, creamy-white subretinal mass within the vitreous cavity.

B-scan ultrasonography results revealed a homogeneous, uncalcified tumor filling two thirds of the eye (Figure 2). Sclera underlying the tumor bulged like a staphyloma. The medial rectus muscle moved freely. Computed tomography results showed an abnormal-shaped, small eye with ectatic or deficient sclera underlying the uncalcified tumor and medial rectus (Figure 3). Coronal T2-weighted magnetic resonance imaging results showed no melanin or blood in the tumor, which was isodense with cerebral cortex (Figure 4). The tumor border was smooth and concave with a vitreous band, possibly persistent hyaloid, extending across the vitreous/subretinal space to the sclera. There was no extraocular extension. The optic nerves and brain appeared normal.

View larger version (44K): [in this window] [in a new window] Figure 2. B-scan ultrasonography results show a homogeneous, uncalcified mass occupying two thirds of the vitreous cavity, overlying the optic nerve, and extending anteriorly to abut the lens. Sclera beneath the tumor suggested a staphyloma. A vitreous band (arrow) was present on the temporal side of the mass.

View larger version (55K): [in this window] [in a new window] Figure 3. Nonenhanced axial computed tomography results show a small right eye with irregular, possibly deficient sclera adjacent to the tumor under the medial rectus muscle (white arrow). The tumor mass was not calcified and did not show extraocular extension.

View larger version (61K): [in this window] [in a new window] Figure 4. Coronal T2-weighted magnetic resonance imaging results confirmed that the tumor did not contain melanin or blood but was isodense with gray matter. A vitreous band, possibly persistent hyaloid, extended superotemporally from the smooth tumor border to the sclera. The eye appears egg-shaped with a bulge in the sclera beneath the tumor medially (white arrow).

Malignant teratoid medulloepithelioma with persistent hyperplastic primary vitreous was suspected. Serial B-scans during 2 weeks suggested growth and change in vitreous density. Eye Cancer Network and International Tumor Board (New York, NY) consultations all recommended enucleation of this blind eye with possible malignancy. The 16 x 17 x 16-mm eye showed no scleral defects. On opening the eye through an inferior, horizontal pupil-optic nerve incision, a solid, uncalcified, homogeneously grayish-white tumor unlike retinoblastoma was found arising in a staphylomatous choroidal coloboma, filling much of the vitreous and abutting the lens anteriorly (Figure 5). Where imaging suggested deficient sclera was a choroid coloboma with scleral ectasia.

View larger version (56K): [in this window] [in a new window] Figure 5. Enucleated eye prior to (A) and after (B) an inferior, horizontal pupil-optic nerve incision. A solid, uncalcified tumor was centered in the inferonasal quadrant over an area of thin sclera with absent pigment epithelium (black arrow). Unlike retinoblastoma, this tumor was uniform and firm.

The tumor, eosinophilic on hematoxylin-eosin stain, resting directly on ectactic sclera in the anterior retina/ciliary region, extended backward across the choroid to the optic nerve (Figure 6A). Areas of dysplastic retina were thrown into focal pseudorosettes in their periphery (Figure 6A). The tumor was composed of brain tissue strongly positive for synaptophysin (Figure 6B). Large, mature, crystal violet–positive neurons (Figure 7A, B, and D); glial, fibrillary, acidic, protein-positive, plump oligodendrocytes; and spindle-shaped astrocytes (Figure 7A and C) were admixed with neuropil containing rare focal calcification. The cornea and anterior chamber were unremarkable. Lens epithelial and bladder cells had migrated into the posterior subcapsular area. The ciliary body was attenuated. The tumor appeared to arise from the retina in some areas (Figure 8A) and the retinal pigment epithelium in others (Figure 8B). The 6-mm, tumor-free optic nerve was atrophic, drawn into the globe under traction (Figure 8B).

View larger version (97K): [in this window] [in a new window] Figure 6. A, A large, well-circumscribed tumor filled approximately 70% of the globe. The sclera external to the tumor was scalloped and thinned (arrow). The retina internal to the tumor was effaced and thrown focally into pseudorosettes (*). The tumor spanned between the lens (L) and the optic nerve (ON). Areas of normal cornea (C) and retina (R) were also seen. The central cavity within the tumor was an artifact (hematoxylin-eosin, original magnification). B, Synaptophysin immunostaining demonstrated diffuse positivity within the tumor and normal retina. The tumor did not appear to invade or arise from the optic nerve, which did not label with synaptophysin. A projection of the tumor extended into the scleral opening of a ciliary nerve (arrow) (synaptophysin, original magnification).

View larger version (152K): [in this window] [in a new window] Figure 7. A, High-power photomicrograph of the tumor demonstrating mature neurons (arrow), oligodendrocytes (diamond-headed arrow), and astrocytes (open arrow) interspersed in neuropil, typical of cerebral gray matter (hematoxylin-eosin). B, Crystal violet stain of mature neurons within the tumor (arrow). The stain bound very strongly to RNA in the rough endoplasmic reticulum of the neuron. Note the prominent nucleolus. C, Glial fibrillary acidic protein in astrocytes (arrows), the most common glia in the tumor. D, A single neuron within the tumor immunolabeled with neurofilament antibody. Note the dendritic processes (D) and large central nucleus (N) typical of most neurons (all images original magnification x400).

View larger version (85K): [in this window] [in a new window] Figure 8. A, Relationship between the tumor (T), choroid (C), and normal retina (R) with the tumor appearing contiguous with the outer retina (arrow) (hematoxylin-eosin, original magnification x40). B, The tumor (T) appeared to have drawn the optic nerve (ON) into the eye. Note the displacement of the retina (R) and apparent continuity of the tumor with the retinal pigment epithelium (RPE) (arrows) (hematoxylin-eosin, original magnification x100).

Comment
Normal brain tissue not communicating with the central nervous system (brain heterotopia) has been reported in the head and neck, rarely in the orbit,^2-5 at the limbus,^6-7 and in 1 case in the anterior segment of an infant's eye.⁸ Intraocular heterotopic brain tissue arising from the retina or anterior retinal pigment epithelium was reported recently.¹ To our knowledge, this is the second report.

Previous authors proposed that when embryonal neurectodermal stem cells segregated outside the central nervous system during development, teratomatous proliferation or true astrocytomas or benign brain heterotopia could result.^{2, 4, 8} In our patient, the tumor appeared to arise from both the retina and retinal pigment epithelium within a coloboma, suggesting abnormal neurectoderm differentiation within the optic cup in the embryonic fissure, causing subsequent microphthalmia and anterior segment maldevelopment. The pathogenesis is uncertain; failure of a clone of pluripotential stem cells in the embryonic fissure to initiate normal retinal development may have occurred. This may be due to a somatic mutation in a gene involved in the retinal signaling pathway, such as CHX-10⁹; PAX6¹⁰; PAX2¹¹; Rx¹²; or sonic hedgehog, SHH,¹³ which are required for vertebrate retinal development. These mutations potentially could leave cortical development as a default pathway for retinal differentiation. Thus, a focal cerebrocortical cell mass arising in the anterior retina/ciliary region may be analogous to experimental eye formation in ectopic locations when the Drosophila gene, eyeless (ey), homologous to mammalian PAX6, drives eye development wherever ectopic expression occurs.¹⁴ A germline deletion in SHH has been associated with iris and uveoretinal colobomas.¹³ We hypothesize in the present case that somatic mutation in such a gene may be causative.

The finding of leukocoria in a child requires thorough evaluation to exclude retinoblastoma or other intraocular malignancies. This neonatal development of an uncalcified, homogeneous intraocular mass in a microphthalmic eye was more consistent with a developmental anomaly than retinoblastoma. With no possible useful vision but potential malignancy, including atypical teratoid medulloepithelioma or retinoblastoma, enucleation of the eye was indicated. This child continues to thrive without needing further medical tests or interventions.

The authors have no relevant financial interest in this article.

This study was supported in part by grants MT15014 (Dr Chan) and 012329 (Dr Gallie) from the National Cancer Institute of Canada, Toronto; a previous grant, 013136, on retinoblastoma from the Canadian Institutes of Health Research, Ottawa, Ontario (Dr Chan); and grants from the Canadian Genetic Diseases Network, Vancouver, British Columbia; the Retinoblastoma Family Association, Richmond Hill, Ontario; and the Royal Arch Masons of Canada, Hamilton, Ontario (Dr Gallie).

AUTHOR INFORMATION

Sarit Patel, MD; Daniel Albert, MD
Madison, Wis

Joanne Dondey, MD; Helen S. L. Chan, MB, BS; Elise Héon, MD; Susan Blaser, MD; Brenda L. Gallie, MD
Toronto, Ontario

Corresponding author and reprints: Brenda L. Gallie, MD, Department of Cancer Informatics, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, 610 University Ave, Toronto, Ontario, Canada M5G 2M9 (e-mail: gallie{at}attglobal.net).

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