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Leukocoria caused by diverse ocular conditions is distinguishable byhistory, characteristic clinical findings, and ancillary imaging. Atypicalcases pose a diagnostic dilemma necessitating enucleation if retinoblastomaor malignancy cannot be excluded. We report a newborn with leukocoria in amicrophthalmic eye containing an uncalcified subretinal mass. Teratoid medulloepitheliomawas suspected. Instead, benign heterotopic brain tissue was found, which toour knowledge has only been reported once before,1 dueto aberrant differentiation of the neurectoderm into cerebral gray matterinstead of the retina.
Report of a Case
A 5-day-old, healthy baby girl with leukocoria of the microphthalmicright eye was seen in the Retinoblastoma Program at the Hospital for SickChildren, 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 rightcornea was clear and the anterior chamber, deep. The iris was hypoplasticwith persistent tunica vasculosa lentis bridging the pupil. The irregularlyshaped 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 untiljust behind the lens.
Digital camera results show aclear cornea; prominent, immature iris vasculature; a small, irregularly shapedlens; 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 tumorfilling two thirds of the eye (Figure 2).Sclera underlying the tumor bulged like a staphyloma. The medial rectus musclemoved freely. Computed tomography results showed an abnormal-shaped, smalleye with ectatic or deficient sclera underlying the uncalcified tumor andmedial rectus (Figure 3). CoronalT2-weighted magnetic resonance imaging results showed no melanin or bloodin the tumor, which was isodense with cerebral cortex (Figure 4). The tumor border was smooth and concave with a vitreousband, possibly persistent hyaloid, extending across the vitreous/subretinalspace to the sclera. There was no extraocular extension. The optic nervesand brain appeared normal.
B-scan ultrasonography resultsshow a homogeneous, uncalcified mass occupying two thirds of the vitreouscavity, overlying the optic nerve, and extending anteriorly to abut the lens.Sclera beneath the tumor suggested a staphyloma. A vitreous band (arrow) waspresent on the temporal side of the mass.
Nonenhanced axial computed tomographyresults show a small right eye with irregular, possibly deficient sclera adjacentto the tumor under the medial rectus muscle (white arrow). The tumor masswas not calcified and did not show extraocular extension.
Coronal T2-weighted magnetic resonanceimaging results confirmed that the tumor did not contain melanin or bloodbut was isodense with gray matter. A vitreous band, possibly persistent hyaloid,extended superotemporally from the smooth tumor border to the sclera. Theeye appears egg-shaped with a bulge in the sclera beneath the tumor medially(white arrow).
Malignant teratoid medulloepithelioma with persistent hyperplastic primaryvitreous was suspected. Serial B-scans during 2 weeks suggested growth andchange in vitreous density. Eye Cancer Network and International Tumor Board(New York, NY) consultations all recommended enucleation of this blind eyewith possible malignancy. The 16 × 17 × 16-mm eye showed no scleraldefects. On opening the eye through an inferior, horizontal pupil-optic nerveincision, a solid, uncalcified, homogeneously grayish-white tumor unlike retinoblastomawas found arising in a staphylomatous choroidal coloboma, filling much ofthe vitreous and abutting the lens anteriorly (Figure 5). Where imaging suggested deficient sclera was a choroidcoloboma with scleral ectasia.
Enucleated eye prior to (A) andafter (B) an inferior, horizontal pupil-optic nerve incision. A solid, uncalcifiedtumor was centered in the inferonasal quadrant over an area of thin sclerawith absent pigment epithelium (black arrow). Unlike retinoblastoma, thistumor was uniform and firm.
The tumor, eosinophilic on hematoxylin-eosin stain, resting directlyon ectactic sclera in the anterior retina/ciliary region, extended backwardacross the choroid to the optic nerve (Figure6A). Areas of dysplastic retina were thrown into focal pseudorosettesin their periphery (Figure 6A).The tumor was composed of brain tissue strongly positive for synaptophysin(Figure 6B). Large, mature, crystalviolet–positive neurons (Figure 7A,B, and D); glial, fibrillary, acidic, protein-positive, plump oligodendrocytes;and spindle-shaped astrocytes (Figure 7Aand C) were admixed with neuropil containing rare focal calcification. Thecornea and anterior chamber were unremarkable. Lens epithelial and bladdercells had migrated into the posterior subcapsular area. The ciliary body wasattenuated. The tumor appeared to arise from the retina in some areas (Figure 8A) and the retinal pigment epitheliumin others (Figure 8B). The 6-mm,tumor-free optic nerve was atrophic, drawn into the globe under traction (Figure 8B).
A, A large, well-circumscribedtumor filled approximately 70% of the globe. The sclera external to the tumorwas scalloped and thinned (arrow). The retina internal to the tumor was effacedand thrown focally into pseudorosettes (*). The tumor spanned between thelens (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 diffusepositivity within the tumor and normal retina. The tumor did not appear toinvade 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).
A, High-power photomicrographof the tumor demonstrating mature neurons (arrow), oligodendrocytes (diamond-headedarrow), and astrocytes (open arrow) interspersed in neuropil, typical of cerebralgray matter (hematoxylin-eosin). B, Crystal violet stain of mature neuronswithin the tumor (arrow). The stain bound very strongly to RNA in the roughendoplasmic reticulum of the neuron. Note the prominent nucleolus. C, Glialfibrillary acidic protein in astrocytes (arrows), the most common glia inthe tumor. D, A single neuron within the tumor immunolabeled with neurofilamentantibody. Note the dendritic processes (D) and large central nucleus (N) typicalof most neurons (all images original magnification ×400).
A, Relationship between the tumor(T), choroid (C), and normal retina (R) with the tumor appearing contiguouswith the outer retina (arrow) (hematoxylin-eosin, original magnification ×40).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 tumorwith the retinal pigment epithelium (RPE) (arrows) (hematoxylin-eosin, originalmagnification ×100).
Normal brain tissue not communicating with the central nervous system(brain heterotopia) has been reported in the head and neck, rarely in theorbit,2-5 atthe limbus,6,7 and in 1case in the anterior segment of an infant's eye.8 Intraocularheterotopic brain tissue arising from the retina or anterior retinal pigmentepithelium was reported recently.1 To ourknowledge, this is the second report.
Previous authors proposed that when embryonal neurectodermal stem cellssegregated outside the central nervous system during development, teratomatousproliferation 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 epitheliumwithin a coloboma, suggesting abnormal neurectoderm differentiation withinthe optic cup in the embryonic fissure, causing subsequent microphthalmiaand anterior segment maldevelopment. The pathogenesis is uncertain; failureof a clone of pluripotential stem cells in the embryonic fissure to initiatenormal retinal development may have occurred. This may be due to a somaticmutation in a gene involved in the retinal signaling pathway, such as CHX-109; PAX610; PAX211; Rx12;or sonic hedgehog, SHH,13 whichare required for vertebrate retinal development. These mutations potentiallycould leave cortical development as a default pathway for retinal differentiation.Thus, a focal cerebrocortical cell mass arising in the anterior retina/ciliaryregion may be analogous to experimental eye formation in ectopic locationswhen the Drosophila gene, eyeless (ey), homologousto mammalian PAX6, drives eye development whereverectopic expression occurs.14 A germlinedeletion in SHH has been associated with iris anduveoretinal colobomas.13 We hypothesizein the present case that somatic mutation in such a gene may be causative.
The finding of leukocoria in a child requires thorough evaluation toexclude retinoblastoma or other intraocular malignancies. This neonatal developmentof an uncalcified, homogeneous intraocular mass in a microphthalmic eye wasmore consistent with a developmental anomaly than retinoblastoma. With nopossible useful vision but potential malignancy, including atypical teratoidmedulloepithelioma 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 previousgrant, 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, RichmondHill, Ontario; and the Royal Arch Masons of Canada, Hamilton, Ontario (DrGallie).
Corresponding author and reprints: Brenda L. Gallie, MD, Departmentof Cancer Informatics, Ontario Cancer Institute/Princess Margaret Hospital,University Health Network, 610 University Ave, Toronto, Ontario, Canada M5G2M9 (e-mail: firstname.lastname@example.org)
Patel S, Albert D, Dondey J, et al. Leukocoria Caused by Intraocular Heterotopic Brain Tissue. Arch Ophthalmol. 2004;122(3):390–393. doi:10.1001/archopht.122.3.390
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