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Clinicopathologic Reports, Case Reports, and Small Case Series
September 2002

Atypical Retinoblastoma Presentations: A Challenge for the Treating Ophthalmologist

Arch Ophthalmol. 2002;120(9):1222-1225. doi:

An intraocular procedure in a child with retinoblastoma represents one of the few situations in which an ophthalmologist can produce a disease that may be fatal to the patient. It is always important to consider retinoblastoma, even in children who are atypical in age or appearance for this disease.

Report of Cases
Case 1

A 19-month-old boy with a medical history of malrotation of the intestines who had recently undergone their surgical repair, was referred for evaluation of leukocoria in his right eye. His ocular history was significant for strabismus at 6 months of age that was attributed to prominent epicanthal folds. At approximately 19 months of age, his right eye clearly deviated, and he was referred to a pediatric ophthalmologist who subsequently referred the patient to the ocular oncology unit at the University of California, San Francisco (UCSF).

On examination at UCSF, the patient demonstrated visual fixation that was not central and not steady in the right eye, with central steady and maintained fixation in the patient's left eye. A 15–prism diopter (PD) exotropic strabismus was observed in the right eye. Intraocular pressures were 19 mm Hg OD and 21 mm Hg OS.

Indirect ophthalmoscopy performed under anesthesia revealed an elevated exophytic mass in the right inferotemporal retina, measuring 10 × 11 × 8 mm (Figure 1). The subretinal mass, which appeared yellow and lipid filled, was associated with a total, exudative retinal detachment. Scattered subretinal lipid, as well as retinal pigment epithelial change, was found throughout the retina. The majority of the retinal vasculature appeared normal, although prominent telangiectatic vessels, confirmed by intraoperative fluorescein angiography, were noted overlying the tumor mass. No intrinsic calcification of the mass was noted on ultrasonography. The left eye demonstrated a normal disc, vessels, macula, and periphery.

Figure 1.
Yellow subretinal mass with associated
subretinal fluid and scattered subretinal lipids.

Yellow subretinal mass with associated subretinal fluid and scattered subretinal lipids.

Orbital and cerebral computed tomographic scans demonstrated right microophthalmia, with a noncalcified minimally enhancing nodular mass along the posterior wall of the right orbit, as well as focal subependymal calcifications. Magnetic resonance imaging revealed cortical tubers and subependymal hamartomas within the brain parenchyma. No giant cell astrocytoma was noted. These radiographic findings were believed to be characteristic of tuberous sclerosis.

The patient was noted as having diffuse ash-leaf spots on dermatologic examination (Figure 2). Infectious serologies for toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus type 1, and herpes simplex virus 2 were negative.

Figure 2.
Hypopigmented macules consistent
with the clinical appearance of ash-leaf spots.

Hypopigmented macules consistent with the clinical appearance of ash-leaf spots.

The differential diagnosis included retinal astrocytoma, Coats disease, persistent hyperplastic primary vitreous, or an atypical presentation of retinoblastoma. Subsequent examination of the right eye was remarkable for an intraocular pressure of 53 mm Hg, iris neovascularization, and a total retinal detachment. The right eye was enucleated and replaced with a hydroxyapatite implant. Pathologic examination results revealed necrotic retinoblastoma with a secondary Coats-like response. There was no involvement of the optic nerve. To date, this child has remained free of retinoblastoma in the orbit and in the contralateral eye for 26 months. The patient was referred to a pediatric neurologist for management of tuberous sclerosis with central nervous system involvement. The child remains asymptomatic from this disease process.

Case 2

A previously healthy 6-year-old boy who had undergone an undiagnostic anterior chamber and vitreous tap in Ecuador was referred to UCSF for further consideration of a mass in his right globe. Findings from an extensive workup for infectious disease performed in Ecuador were negative. He had been given a preliminary diagnosis of Coats disease.

He first visited UCSF under a regimen of topical fluorometholone and atropine for his right eye. On examination, his visual acuity was no light perception OD and 20/20 OS. Leukocoria was present in the right eye. Slitlamp examination of his right eye was remarkable for shallow and inferior iridocorneal adhesions, a neovascularized iris, and retrolenticular opacification in the anterior vitreous. Intraocular pressure was 45 mm Hg OD. Indirect ophthalmoscopy revealed a detached and diffusely thickened retina without a visible focal mass. Ultrasonography confirmed a detached retina with rare intraretinal calcification and no focal mass lesion. Computed tomographic scans demonstrated high attenuation of the right vitreous, suggesting that the vitreous was filled with proteinaceous material. Additionally, 2 calcifications were seen within the anterolateral aspect of the globe.

The differential diagnosis included Coats disease with dystrophic calcification; however, given the results of the diagnostic studies, retinoblastoma could not be excluded. With no light perception visual acuity and rapidly increasing intraocular pressure, the blind eye was enucleated.

Pathologic inspection revealed diffuse retinoblastoma with an extensive necrotic tumor. Focal areas of calcification invaded the optic nerve but did not extend posterior to the lamina cribrosa. Results of a full metastatic workup were negative; however, since this child had previously had a drainage procedure and an anterior chamber tap, the UCSF tumor board recommended 6 months of adjuvant chemotherapy. The boy completed 6 cycles of combination carboplatin, etoposide, and vincristine, which he tolerated well. He has relocated to the United States and receives regular follow-up monitoring. To date, after 32 months of follow-up, he continues to be without evidence of retinoblastoma recurrence.

Case 3

A previously healthy 9-year-old girl visited her ophthalmologist with a retinal detachment following trauma to her left eye from a baseball. She was found to have a solid retinal detachment with white flocculent material under the retina and within the vitreous cavity, though she denied having any visual symptoms. A review of family photographs showed evidence of left eye leukocoria lasting for 30 months.

Examination at UCSF demonstrated a visual acuity of 20/20 OD and no light perception OS. Intraocular pressures were 16 mm Hg OD and 20 mm Hg OS. Slitlamp examination showed diffuse rubeosis iriditis in the left eye, as well as snow-white material in the vitreous that aggregated into clumps and was without intrinsic vasculature (Figure 3). A shallow and diffuse retinal detachment was observed posteriorly. On fluorescein angiography, a posterior tumor mass was noted in the left eye, along with vitreous opacities and iris rubeosis. Ultrasonography failed to demonstrate any intrinsic calcification.

Figure 3.
Slitlamp photograph of vitreous
cells as the clinical presentation of retinoblastoma in a 9-year-old.

Slitlamp photograph of vitreous cells as the clinical presentation of retinoblastoma in a 9-year-old.

During examination while the patient was under anesthesia, neither normal retinal structures nor the optic nerve could be visualized. The vitreous demonstrated a confluent ocular process that had the appearance of inflammation, but that potentially represented vitreous seeding from retinoblastoma.

Computed tomographic scans demonstrated a high-density mass involving her posterior and superolateral left globe. The mass was without intrinsic calcification and was thought unlikely to be a retinoblastoma, especially in light of the child's advanced age.

The differential diagnosis included a massive reaction in the vitreous cells to an inflammatory or infectious process vs retinoblastoma. Since the eye was blind as a result of iris neovascularization, an enucleation was performed.

Pathologic inspection revealed necrotic retinoblastoma cells, which spared the choroid but invaded the optic nerve posterior to the lamina cribrosa. Results of a systemic workup for metastasis were negative. The patient's case was presented to the UCSF tumor board, which recommended adjuvant chemotherapy. She underwent a 6-month course of carboplatin, etoposide, and vincristine, and to date, she has been without recurrence for 16 months.

Comment

Atypical cases of retinoblastoma may lead to diagnostic dilemmas. In the first case, a 19-month-old boy was referred for leukocoria. The diagnosis of retinoblastoma was complicated by magnetic resonance imaging findings consistent with tuberous sclerosis. This made the possibility of an intraocular astrocytic hamartoma likely, since approximately half of all patients with tuberous sclerosis demonstrate retinal hamartomas.1 Atypical retinal astrocytomas with peculiar neovascularization have been reported.2 The eye was also judged to be small, involving persistent hyperplastic primary vitreous in the differential diagnosis. The clinical presentation, however, was most consistent with Coats disease, and retinoblastoma with a prominent Coats-like response was confirmed by the pathology report. No evidence of intrinsic calcification was found within this tumor.

In the second case, a 6-year-old boy was referred from Ecuador with a diagnosis of Coats disease. The results of clinical imaging scans at UCSF suggested proteinaceous material within the vitreous and no focal tumor mass. However, the presence of calcification on computed tomographic scans, which could have been consistent with dystrophic calcification in Coats disease, increased suspicion for retinoblastoma. Use of contrast magnetic resonance imaging has increased the sensitivity in distinguishing Coats disease from retinoblastoma.3 Enhancement of detached sensory retina with the absence of intraocular enhancement following gadolinium–diethylenetriamine pentaacetic acid (DPTA) treatment favors a diagnosis of Coats disease.4 Some difficulty remains, however, in differentiating retinoblastoma from advanced Coats disease.5 Despite the older age at presentation, retinoblastoma was confirmed histopathologically. He unfortunately underwent 6 months of adjuvant chemotherapy because of the procedure that was performed in Ecuador.

In the third case, a 9-year-old girl had a clinical appearance suggestive of uveitis. The cellular material that filled the vitreal space showed no intrinsic calcification and was without intrinsic vascularity. Because the child was 9 years old at the time of examination, retinoblastoma was, again, a relatively low consideration. Although retinoblastoma becomes less frequent with older age, it has been described in adult populations.6 Should this child have demonstrated effective vision, a vitreous aspirate and biopsy (as recommended by several retina specialists) could have been performed. Children with retinoblastoma undergoing intraocular procedures may require bone marrow transplantation for cure. Even with aggressive treatment, many succumb to disseminated disease once the integrity of the globe has been violated by an intraocular procedure.

In summary, the treating ophthalmologist should retain a high index of suspicion for retinoblastoma in all children with intraocular disease, even those who present with an atypical appearance or at an advanced age. Children with no view of the posterior pole who have histories of trauma and hyphema may harbor occult retinoblastoma. Children with uveitic or Coats-like scenarios may also represent unusual manifestations of this disease. Unless retinoblastoma is considered, improper actions may be undertaken, resulting in a potential increase in morbidity and mortality for patients with this disease.

Corresponding author: Joan M. O'Brien, MD, Ocular Oncology Division, Department of Ophthalmology, University of California San Francisco, 10 Koret Way, Room K-301, Box 0730, San Francisco, CA 94143-0730 (e-mail: aleja@itsa.ucsf.edu).

References
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Nyboer  JHRobertson  DMGomez  MR Retinal lesions in tuberous sclerosis. Arch Ophthalmol. 1976;941277- 1280Article
2.
Jost  BFOlk  RJ Atypical retintis proliferans, retinal telangiectasis, and vitreous hemorrhage in a patient with tuberous sclerosis. Retina. 1986;653- 56Article
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Kaufamn  LMMafee  MFSong  CD Retinoblastoma and simulating lesions: role of CT, MR imaging and use of Gd-DTPA contrast enhancement. Radiol Clin North Am. 1998;361101- 1117Article
4.
Edward  DAMafee  MFGarcia-Valenzuela  EGWeiss  RA Coats' disease and persistent hyperplastic primary vitreous: role of MR imaging and CT. Radiol Clin North Am. 1998;361119- 1131Article
5.
Steidl  SMHirose  TSang  DHartnett  ME Difficulties in excluding the diagnosis of retinoblastoma in cases of advanced Coats' disease: a clinicopathologic report. Ophthalmologica. 1996;210336- 400Article
6.
Biswas  JMani  BShanmugam  MP  et al.  Retinoblastoma in adults: report of three cases and review of the literature. Surv Ophthalmol. 2000;44409- 414Article
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