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Clinical Spectrum of Diffuse Infiltrating Retinoblastoma in 34 Consecutive Eyes
Clinical Spectrum of Diffuse Infiltrating Retinoblastoma in 34 Consecutive Eyes Carol L. Shields, MD, Fariba Ghassemi, MD, Samuray Tuncer, MD, Archana Thangappan, BS, Jerry A. Shields, MD Purpose: To evaluate the clinical features and management of diffuse infiltrating retinoblastoma. Design: Retrospective case series. Participants: Thirty-four eyes in 32 patients. Methods: The patients’ records were reviewed for patient and tumor features, ocular management, histopathologic findings, and patient survival. Main Outcome Measures: Clinical features, tumor management, and patient survival. Results: Of 1507 patients with retinoblastoma, only 32 (2%) were classified with diffuse infiltrating retinoblastoma. The mean age at diagnosis was 4 years (range 1.5–16 years). The referring diagnoses included retinoblastoma (26 eyes, 76%), uveitis (3, 9%), Coats disease (1, 3%), trauma (1, 3%), and unspecified retinal problem (3, 9%). The anterior segment displayed tumor seeds on the corneal endothelium (8, 24%), cornea stromal edema (3, 9%), pseudohypopyon (11, 32%), hyphema (3, 9%), iris neovascularization (17, 50%), and iris tumor nodules (6, 18%). The posterior segment revealed extensive ill-defined retinoblastoma infiltrating the retina for a mean basal diameter of 20 mm and overall flat growth, sometimes with undulating retinal thickening. Overlying extensive vitreous tumor seeds (31, 91%) and vitreous hemorrhage (8, 24%) were noted. Calcification was present on ultrasonography (27/34, 79%) and computed tomography (8/9, 89%). Enucleation was performed for all 34 eyes, and there were no cases of metastases at 47 months follow-up. Conclusions: Diffuse infiltrating retinoblastoma can masquerade as uveitis or unexplained hyphema or keratic precipitates. Suspicion for retinoblastoma is important. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2008;115:2253–2258 © 2008 by the American Academy of Ophthalmology.
Retinoblastoma classically manifests as a solitary or multifocal, well-circumscribed, yellow-white retinal mass with dilated feeding vessels. Initially, a small tumor appears as a translucent, often subtle intraretinal mass. As the tumor enlarges, it assumes vertical and horizontal growth to a round nodule with an exophytic, endophytic, or combined growth pattern.1 Exophytic retinoblastoma generally appears as a moderate to large tumor with overlying subretinal fluid, whereas endophytic tumor appears as a mass with seeding into the vitreous cavity. A rare growth pattern is diffuse infiltrating retinoblastoma where the tumor assumes a relatively flat, ill-defined horizontal growth along the retinal tissue with little vertical growth and little definition of mass.1–3 Diffuse retinoblastoma can lead to anterior segment seeding with pseudohypopyon and intraocular hemorrhage, further confusing the findings. Often this appearance is mistaken for uveitis, unexplained vitreous hemorrhage, hyphema, or even endophthalmitis. In this report, we describe the clinical features of diffuse infiltrating retinoblastoma in 34 eyes.
Materials and Methods A retrospective chart review was performed on all patients with the diagnosis of retinoblastoma who were examined and managed by the Oncology Service at Wills Eye Institute of Thomas Jefferson © 2008 by the American Academy of Ophthalmology Published by Elsevier Inc.
University between June of 1974 and February of 2008. Institutional review board approval from Wills Eye Institute was received. Those patients with the diagnosis of diffuse infiltrating retinoblastoma were selected for further analysis. Diffuse infiltrating retinoblastoma was defined as a relatively flat, ill-defined, horizontal growth of tumor with a minimal vertical component.2– 4 Each patient was evaluated for age, race, sex, related ocular symptoms, tumor laterality, and hereditary pattern. The referring diagnosis and previous treatments elsewhere were recorded. The clinical features at our initial examination included data on visual acuity, strabismus, and intraocular pressure, and corneal, iris, and anterior chamber findings. The posterior segment findings included tumor size and location, number of quadrants involved with tumor or seeding, and extent of retinal detachment. Histopathologic findings included tumor differentiation, necrosis, calcification, and tumor invasion into the surrounding structures. The Reese Ellsworth Classification and International Classification of Retinoblastoma were listed for each eye. Ocular management, histopathology findings, and ultimate patient outcomes were listed.
Results Of 1507 patients with retinoblastoma, there were 34 eyes in 32 patients (2%) classified as having diffuse infiltrating retinoblastoma. The mean (median) follow-up was 47.2 months (47.2 months). The demographic features are listed in Table 1. The mean age at presentation was 4 years. The condition affected 1 eye in 30 patients and both eyes in 2 patients. The referral diagnoses are ISSN 0161-6420/08/$–see front matter doi:10.1016/j.ophtha.2008.07.003
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Ophthalmology Volume 115, Number 12, December 2008 Table 1. Diffuse Infiltrating Retinoblastoma in 34 Eyes of 32 Patients: Demographic Findings Feature Age at diagnosis (y) (n ⫽ 32 patients) Mean (median, range) Race (n ⫽ 32 patients) Caucasian Hispanic African American Sex (n ⫽ 32 patients) Male Female Family history of retinoblastoma (n ⫽ 32 patients) Absent Present Affected eye (n ⫽ 34 eyes) Right Left Laterality (n ⫽ 32 patients) Unilateral Bilateral* History of trauma (n ⫽ 32 patients) Absent Present
No. (%) (n ⴝ 32 patients, 34 eyes) Feature 4 (3.5, 1.5–16) 26 (82) 4 (12) 2 (6) 19 (61) 13 (39)
31 (97) 1 (3) 18 (53) 16 (47) 27 (85) 5 (15) 27 (85) 5 (15)
*Of these 5 bilateral cases, 2 had bilateral diffuse retinoblastoma.
listed in Table 2. Eight eyes (24%) were referred with diagnoses other than retinoblastoma, including uveitis, Coats disease, and trauma. The anterior segment findings are listed in Table 3. Seventeen of 18 eyes (94%) in preverbal children were no fix or follow and 11 of 16 eyes (69%) in verbal children showed 20/200 or worse visual acuity. The most common anterior segment clinical findings included iris neovascularization (50%), tumor-induced pseudohypopyon (32%) or free-floating anterior chamber cells (32%), tumor seeds on the corneal endothelium (24%), and conjunctival injection (18%) (Fig 1). The tumor findings and related posterior segment features are listed in Table 4 (Fig 2). In all cases, the retinoblastoma was ill-defined without discrete tumor mass and the mean basal tumor diameter was 21 mm. Clinically, the tumors appeared as ill-defined thickening of the retina, but ultrasonographic measurement of the tumor apex (thickness) was a mean of 9 mm. This measurement included the tumor and underlying subretinal fluid down to the choroid. Tumor seeding into the vitreous (91%) or subretinal space (59%) and vitreous hemorrhage (24%) was common. The diagnostic testing results are listed in Table 5 and revealed lack of intraocular calcification by ultrasonography in 7 of 34 eyes (21%) and by computed tomography in 1 of 9 eyes (11%) (Fig 2). In those Table 2. Diffuse Infiltrating Retinoblastoma in 34 Eyes of 32 Patients: Referral Diagnosis Referring Diagnosis
No. (%) (n ⴝ 34 eyes)
Retinoblastoma Uveitis Coats disease Trauma Endophthalmitis Nonspecific retinal problem
26 (76) 3 (9) 1 (3) 1 (3) 0 (0) 3 (9)
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Table 3. Diffuse Infiltrating Retinoblastoma in 34 Eyes of 32 Patients: Visual Acuity and Anterior Segment Findings at Initial Examination
Visual acuity (n ⫽ 34 eyes) Verbal children (n ⫽ 16 eyes) 20/20–20/40 20/50–20/100 20/200–hand motions Light perception, no light perception Preverbal children (n ⫽ 18 eyes) Fix and follows No fix or follow Intraocular pressure (n ⫽ 34 eyes) Mean mmHg (median, range) IOPⱕ22 mmHg IOP⬎22 mmHg Ocular alignment (n ⫽ 32 patients) Orthophoria Exotropia Esotropia Anterior segment findings* (n ⫽ 34 eyes) Eyelid edema Conjunctiva edema Conjunctiva injection Cornea endothelium with tumor seeds Cornea stromal edema Cornea band keratopathy Anterior chamber free-floating tumor cells Anterior chamber tumor pseudohypopyon Anterior chamber hyphema Iris tumor seeds Iris neovascularization Iris heterochromia Lens cataract
No. (%) (n ⴝ 32 patients, 34 eyes)
2 (6) 3 (9) 5 (15) 6 (18) 1 (3) 17 (52) 25 (24, 10–51) 17 (50%) 17 (50%) 24 (76) 5 (15) 3 (9) 2 (6) 1 (3) 6 (18) 8 (24) 3 (9) 2 (6) 11 (32) 11 (32) 3 (9) 6 (18) 17 (50) 6 (18) 5 (15)
*Some patients had more than one finding.
eyes with evident calcification within tumor, the finding was minimal. All 34 eyes were managed with enucleation. Histopathology revealed retinoblastoma with poorly differentiated tumor (85%) and necrosis (88%) (Table 6). Iris neovascularization was found in 21 eyes (62%). Tumor invasion was found in the anterior chamber (47%), trabecular meshwork (44%), iris (41%), ciliary body (38%), choroid (12%), and postlaminar optic nerve (18%). Tumor invasion into the anterior chamber, optic nerve, choroid, or sclera was present in 22 eyes (single site in 9 patients, multiple sites in 13 patients) and absent in 12 eyes. On the basis of histopathologic findings, there were 16 patients who required chemotherapy for prevention of metastasis for a combination of reasons, including optic nerve invasion (n ⫽ 7), extraocular extension (n ⫽ 3), anterior chamber involvement (n ⫽ 9), lymphadenopathy with tumor (n ⫽ 1), and previous pars plana vitrectomy (n ⫽ 3). No patients developed further metastasis during a mean 47-month follow-up period.
Discussion There are several growth patterns of retinoblastoma, including exophytic, endophytic, mixed endophytic-exophytic,
Shields et al 䡠 Clinical Spectrum of Diffuse Infiltrating Retinoblastoma Pathology Department at the Institute of Ophthalmology in London showed this growth pattern. Most patients were older, and the tumor growth rate was suspected to be slow. In addition, there was a notable lack of tumor rosettes. Since these early histopathologic observations, little has been published on diffuse infiltrating retinoblastoma. Individual case reports and small case series have highlighted clinical features such as pseudohypopyon, hyphema, uveitis, and the unusual finding of heritable diffuse retinoblastoma.6 –13 Bhatnagar and Vine14 reviewed the published literature in 1991 and found only 34 cases, mostly case reports. They commented that computed tomography and ultrasonography were not helpful and that anterior chamber aspiration was often necessary to establish the diagnosis. Table 4. Diffuse Infiltrating Retinoblastoma in 34 Eyes of 32 Patients: Posterior Segment Findings at Initial Examination Feature Figure 1. Anterior segment findings in diffuse retinoblastoma demonstrating tumor pseudohypopyon in a 6-year-old patient (A), 16-year-old patient (B), 6-year-old patient (C), and 2-year-old patient (D). The referring diagnosis was uveitis (A, C) and retinoblastoma (B, D).
intraretinal, diffuse infiltrating, and spontaneous regression/ arrest (retinocytoma/retinoma).1,4,5 Intraretinal retinoblastoma refers to a small tumor that grows within the retina and does not produce subretinal fluid, subretinal seeds, or vitreous seeds.1 According to a recognized ophthalmic pathology textbook, diffuse infiltrating retinoblastoma is the least common growth pattern and often the most difficult to recognize clinically.4 Diffuse infiltrating retinoblastoma grows “diffusely within the retina without greatly thickening it.”4 There is no clear-cut definition or guideline for this tumor, but generally it is identified by flat infiltration of retinoblastoma within the retina without discrete nodularity. It can show a partially endophytic growth pattern, with tumor seeding into the vitreous, zonule, and anterior chamber. There are other cancers that can assume a flat growth pattern like pagetoid invasion of sebaceous carcinoma, morpheaform basal cell carcinoma, diffuse choroidal melanoma, and superficial spreading cutaneous melanoma. In 1958, Ashton suggested the term “diffuse infiltrating retinoblastoma” to describe the unusual nature of this flat neoplasm that did not produce a tumor mass within the retina.2 Several single case reports were recognized. In 1960, Schofield2 was the first to report on a series of eyes (n ⫽ 4) with diffuse retinoblastoma that were examined in the pathology laboratory at the Institute of Ophthalmology in London. Of these 4 eyes, the clinical features included tumor-induced pseudohypopyon (n ⫽ 4) and elevated intraocular pressure (n ⫽ 3), and all were later discovered to have retinoblastoma after aspiration of the anterior chamber. In 1971, Morgan3 described the pathologic features in 6 additional cases with illustrations of dramatically flat retinoblastoma on histopathology with tumor cells lining the retina, pars plana, pars plicata, and iris. He commented that only 10 of 720 eyes (1.4%) with retinoblastoma in the
Reese-Ellsworth Classification Group I Group II Group III Group IV Group V International Classification of Retinoblastoma Group A Group B Group C Group D Group E Location main tumor (n ⫽ 34 eyes) Superior Temporal Inferior Nasal Macula Basal diameter (mm) main tumor (n ⫽ 34 eyes) Mean (median, range) Thickness* (mm) main tumor (n ⫽ 34 eyes) Mean (median, range) Other posterior segment findings (n ⫽ 34 eyes) Vitreous tumor seeds† Vitreous tumor seeds extent 1 quadrant 2 quadrant 3 quadrant 4 quadrant Vitreous hemorrhage Subretinal fluid Subretinal tumor seeds Retinal telangiectasia NVE, NVD
No. (%) (n ⴝ 32 patients, 34 eyes) 0 (0) 0 (0) 0 (0) 0 (0) 34 (100)
0 (0) 0 (0) 0 (0) 6 (18) 28 (82) 3 (9) 6 (18) 11 (31) 7 (21) 7 (21)
21 (22, 10–40)
9 (8, 2–19)
31 (91) 0 (0) 1 (3) 1 (3) 29 (85) 8 (24) 24 (71) 20 (59) 1 (3) 1 (3)
NVD ⫽ neovascularization optic disc; NVE ⫽ neovascularization elsewhere. *Thickness was measured from the apex of the retinal tumor to the choroid and included retinal pathology and subretinal fluid. † In 1 patient with bilateral diffuse retinoblastoma, pars plana vitrectomy was performed bilaterally before referral.
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Figure 2. Clinical features, imaging, and gross pathology findings in diffuse retinoblastoma in a 5-year-old girl (A, B, C), 18-month-old girl (D, E, F), 4-year-old girl (G, H, I), and 2-year-old girl (J, K, L). Barely visible anterior chamber tumor cells (J) to frank pseudohypopyon (A) were visible. Ultrasonography revealed intraocular calcium (E) or lack of calcium (H), and computed tomography revealed calcium (L). Gross pathology showed diffusely minimally (C) or markedly (F, I) thickened retina from infiltrative retinoblastoma.
Our more contemporary series is the first large clinical series describing this unusual form of retinoblastoma in 34 additional eyes. Similar to Morgan’s3 findings from a pathology laboratory, we found 32 (2%) of 1507 patients with clinical evidence of retinoblastoma from the Ocular Oncology Service at Wills Eye Institute in Philadelphia displayed diffuse growth pattern, and older patient age was common (mean of 4 years). One of our intentions was to describe the spectrum of clinical features of this tumor. Salient features included poor visual acuity of 20/200 or worse in 69% (11/16 eyes of verbal children) and no fix or follow in 94% (17/18 eyes of preverbal children), iris neovascularization (50%), tumorinduced pseudohypopyon (32%), tumor seeds on iris (18%) or corneal endothelium (24%), and hyphema (9%). Less common features included eyelid edema (6%), conjunctival
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edema (3%), conjunctival injection (18%), corneal edema (9%), band keratopathy (6%), cataract (15%), and vitreous hemorrhage (24%). Nearly all eyes (91%) had visible vitreous tumor seeds, and most often the seeds involved all 4 quadrants (85%). Many of these features overlap findings with ocular inflammatory diseases or trauma; thus, there is difficulty in diagnosis. Ocular imaging can assist with differentiating retinoblastoma from uveitis and other causes of retinal detachment. Retinoblastoma classically displays intralesional calcification on ultrasonography, but many cases of diffuse retinoblastoma have had no demonstrable calcium with these studies.1,14,15 In one retrospective review of the literature, 4 of 28 eyes with diffuse retinoblastoma had calcification on histopathology.14 In our series, carefully performed ultrasonography in all 34 eyes showed retinal detachment (56%),
Shields et al 䡠 Clinical Spectrum of Diffuse Infiltrating Retinoblastoma vitreous opacification (76%), and presence of echoes consistent with calcium (79%). However, these echoes were often subtle, single echodensities in the vitreous and much less evident than those seen with classic nodular retinoblastoma. Computed tomography was available in 9 eyes, and disclosed intraocular calcification was observed in 89%. Histopathologically, some degree of dystrophic calcification was noted on routine sections within the tumor in 19 (56%) of the 34 eyes. Perhaps the improved resolution of ultrasound and computed tomography technology in more recent years, with attention to presence of calcium, has allowed improved detection. In every case, the diagnosis was made on clinical examination. In no case was fine-needle aspiration biopsy necessary to establish the diagnosis. Needle biopsy could be dangerous, because it could seed the tumor into the subconjunctival or orbital space and create a higher risk for metastatic disease.16,17 Pars plana vitrectomy had been performed before referral in 3 eyes of 2 patients, establishing the diagnosis histopathologically. All 3 eyes were enucleated, and both patients were treated with systemic chemotherapy for 6 months with no recurrence or metastasis at 4.2 and 10.8 years follow-up, respectively.18 In all cases, enucleation was necessary because of the advanced features of the malignancy. Histopathologically, most cases were poorly differentiated (85%). Necrosis was prominent (88%), and this factor may have contributed to the higher than expected presence of dystrophic calcification in our series. Tumor invasion was present in the anterior chamber (47%), trabecular meshwork (44%), iris (41%), ciliary body (38%), choroid (12%), and optic nerve deep to the lamina cribrosa (18%). Most of these are high-risk features that promote a greater risk for metastatic disease.19 Sixteen of the 32 patients required adjuvant chemotherapy to prevent metastasis; and no patient developed metastatic disease at a mean 4-year follow-up. Diffuse infiltrating retinoblastoma is a growth pattern found clinically in only 2% of eyes with retinoblastoma. This form of retinoblastoma often presents at an advanced stage and later than other clinical growth patterns, at a mean age of 4 years and up to 16 years in this series, compared with an overall Table 5. Diffuse Infiltrating Retinoblastoma in 34 Eyes of 32 Patients: Diagnostic Testing Diagnostic Test Ultrasonography (n ⫽ 34 eyes) Visible mass Calcification of tumor or seeds Retinal detachment Vitreous opacity Computed tomography (n ⫽ 9) Visible mass Calcification of tumor or seeds Retinal detachment Vitreous opacity Magnetic resonance imaging (n ⫽ 7) Visible mass Mass enhancement Retinal detachment Vitreous opacity
Table 6. Diffuse Infiltrating Retinoblastoma in 34 Eyes of 32 Patients: Histopathologic Findings Features Tumor differentiation Poorly differentiated Well differentiated Mixed Tumor findings Necrosis Rosettes Calcification dystrophic Invasion into ocular tissues Cornea Anterior chamber Trabecular meshwork Uvea Iris Ciliary body Choroid Zonule Vitreous Subretina Subretinal pigment epithelium Optic nerve Invasion to lamina cribrosa Invasion beyond lamina cribrosa Sclera Orbit* Iris neovascularization
No. (%) (n ⴝ 32 patients, 34 eyes) 29 (85) 3 (9) 2 (6) 30 (88) 13 (38) 19 (56) 1 (3) 16 (47) 15 (44) 14 (41) 13 (38) 4 (12) 7 (21) 28 (82) 19 (56) 17 (50) 11 (32) 6 (18) 1 (3) 1 (3) 21 (62)
*One patient with bilateral diffuse retinoblastoma who had pars plana vitrectomy performed before referral was found to have extraocular extension at the sclerotomy site.
mean age of approximately 18 months for the total patient population with retinoblastoma. Most patients present with advanced features of anterior segment invasion, glaucoma, and prelaminar or postlaminar optic nerve extension. Any child with signs of uveitis, hyphema, hypopyon, vitreous hemorrhage, or retinal detachment should be evaluated for retinoblastoma. Even if ocular imaging is negative for calcification, fundus evaluation by experienced examiners should be performed, and interventional procedures should be avoided until the diagnosis of retinoblastoma is clearly excluded.
No. (%) (n ⴝ 32 patients, 34 eyes) 32 (94) 27 (79) 19 (56) 26 (76) 6 (67) 8 (89) 2 (22) 1 (11) 6 (86) 4 (58) 3 (42) 0 (0)
References 1. Shields JA, Shields CL. Retinoblastoma: Introduction, Genetics, Clinical Features, Classification. In: Intraocular Tumors: An Atlas and Textbook. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:293–317. 2. Schofield PB. Diffuse infiltrating retinoblastoma. Br J Ophthalmol 1960;44:35– 41. 3. Morgan G. Diffuse infiltrating retinoblastoma. Br J Ophthalmol 1971;55:600 – 6. 4. McLean IW. Retinoblastomas, retinocytomas, and pseudoretinoblastomas. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and Textbook. 4th ed. vol. 2. Philadelphia, PA: Saunders; 1996; 1332– 438.
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Ophthalmology Volume 115, Number 12, December 2008 5. Shields CL, Mashayekhi A, Au AK, et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 2006;113:2276 – 80. 6. Nicholson D, Norton EW. Diffuse infiltrating retinoblastoma. Trans Am Ophthalmol Soc 1980;78:265– 89. 7. Shields JA, Shields CL, Eagle RC, Blair CJ. Spontaneous pseudohypopyon secondary to diffuse infiltrating retinoblastoma. Arch Ophthalmol 1988;106:1301–2. 8. Mansour AM, Greenwald MJ, O’Grady R. Diffuse infiltrating retinoblastoma. J Pediatr Ophthalmol Strabismus 1989;26: 152– 4. 9. Foster BS, Mukai S. Intraocular retinoblastoma presenting as ocular and orbital inflammation. Int Ophthalmol Clin 1996; 36:153– 60. 10. Shields JA, Shields CL, Materin M. Diffuse infiltrating retinoblastoma presenting as a spontaneous hyphema. J Pediatr Ophthalmol Strabismus 2000;37:311–2. 11. Kao LY. Diffuse infiltrating retinoblastoma: an inherited case. Retina 2000;20:217–9. 12. Materin MA, Shields CL, Shields JA, Eagle RC Jr. Diffuse infiltrating retinoblastoma simulating uveitis in a 7-year-old boy. Arch Ophthalmol 2000;118:442–3.
13. All-Ericsson C, Economou MA, Landau I, et al. Uveitis masquerade syndromes: diffuse retinoblastoma in an older child. Acta Ophthalmol Scand 2007;85:569 –70. 14. Bhatnagar R, Vine AK. Diffuse infiltrating retinoblastoma. Ophthalmology 1991;98:1657– 61. 15. Brisse HJ, Lumbroso L, Freneaux PC, et al. Sonographic, CT, and MR imaging findings in diffuse infiltrative retinoblastoma: report of two cases with histologic comparison. AJNR Am J Neuroradiol 2001;22:499 –504. 16. O’Hara BJ, Ehya H, Shields JA, et al. Fine needle aspiration biopsy in pediatric ophthalmic tumors and pseudotumors. Acta Cytol 1993;37:125–30. 17. Shields CL, Manquez ME, Ehya H, et al. Fine-needle aspiration biopsy of iris tumors in 100 consecutive cases: technique and complications. Ophthalmology 2006;113:2080 – 6. 18. Shields CL, Honavar S, Shields JA, et al. Vitrectomy in eyes with unsuspected retinoblastoma. Ophthalmology 2000;107: 2250 –5. 19. Honavar SG, Singh AD, Shields CL, et al. Postenucleation adjuvant therapy in high-risk retinoblastoma. Arch Ophthalmol 2002;120:923–31.
Footnotes and Financial Disclosures Originally received: April 23, 2008. Final revision: May 29, 2008. Accepted: July 10, 2008. Available online: October 29, 2008.
Manuscript no. 2008-506.
Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania. Supported by the Retina Research Foundation of the Retina Society in Cape Town, South Africa (CLS); the Scientific and Technical Research Council of the Turkish Republic (TUBITAK), Ankara, Turkey (ST); the Paul Kayser International Award of Merit in Retina Research, Houston, Texas (JAS); a donation from Michael, Bruce, and Ellen Ratner, New York, New York (JAS, CLS); the Mellon Charitable Giving from the Martha W. Rogers Charitable Trust, Philadelphia, Pennsylvania (CLS); the
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LuEsther Mertz Retina Research Foundation, New York, New York (CLS); and the Eye Tumor Research Foundation, Philadelphia, Pennsylvania (CLS, JAS). Financial Disclosure(s): The funders had no role in the design and conduct of the study; collection, analysis, and interpretation of the data; and preparation, review, or approval of the article. Carol L. Shields, MD, has had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. Correspondence: Carol L. Shields, MD, Ocular Oncology Service, Suite 1440, Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107. E-mail: carol.shields@ shieldsoncology.com.
Retinoblastoma classically manifests as a solitary or multifocal, well-circumscribed, yellow-white retinal mass with dilated feeding vessels. Initially, a small tumor appears as a translucent, often subtle intraretinal mass. As the tumor enlarges, it assumes vertical and horizontal growth to a round nodule with an exophytic, endophytic, or combined growth pattern.1 Exophytic retinoblastoma generally appears as a moderate to large tumor with overlying subretinal fluid, whereas endophytic tumor appears as a mass with seeding into the vitreous cavity. A rare growth pattern is diffuse infiltrating retinoblastoma where the tumor assumes a relatively flat, ill-defined horizontal growth along the retinal tissue with little vertical growth and little definition of mass.1–3 Diffuse retinoblastoma can lead to anterior segment seeding with pseudohypopyon and intraocular hemorrhage, further confusing the findings. Often this appearance is mistaken for uveitis, unexplained vitreous hemorrhage, hyphema, or even endophthalmitis. In this report, we describe the clinical features of diffuse infiltrating retinoblastoma in 34 eyes.
Materials and Methods A retrospective chart review was performed on all patients with the diagnosis of retinoblastoma who were examined and managed by the Oncology Service at Wills Eye Institute of Thomas Jefferson © 2008 by the American Academy of Ophthalmology Published by Elsevier Inc.
University between June of 1974 and February of 2008. Institutional review board approval from Wills Eye Institute was received. Those patients with the diagnosis of diffuse infiltrating retinoblastoma were selected for further analysis. Diffuse infiltrating retinoblastoma was defined as a relatively flat, ill-defined, horizontal growth of tumor with a minimal vertical component.2– 4 Each patient was evaluated for age, race, sex, related ocular symptoms, tumor laterality, and hereditary pattern. The referring diagnosis and previous treatments elsewhere were recorded. The clinical features at our initial examination included data on visual acuity, strabismus, and intraocular pressure, and corneal, iris, and anterior chamber findings. The posterior segment findings included tumor size and location, number of quadrants involved with tumor or seeding, and extent of retinal detachment. Histopathologic findings included tumor differentiation, necrosis, calcification, and tumor invasion into the surrounding structures. The Reese Ellsworth Classification and International Classification of Retinoblastoma were listed for each eye. Ocular management, histopathology findings, and ultimate patient outcomes were listed.
Results Of 1507 patients with retinoblastoma, there were 34 eyes in 32 patients (2%) classified as having diffuse infiltrating retinoblastoma. The mean (median) follow-up was 47.2 months (47.2 months). The demographic features are listed in Table 1. The mean age at presentation was 4 years. The condition affected 1 eye in 30 patients and both eyes in 2 patients. The referral diagnoses are ISSN 0161-6420/08/$–see front matter doi:10.1016/j.ophtha.2008.07.003
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Ophthalmology Volume 115, Number 12, December 2008 Table 1. Diffuse Infiltrating Retinoblastoma in 34 Eyes of 32 Patients: Demographic Findings Feature Age at diagnosis (y) (n ⫽ 32 patients) Mean (median, range) Race (n ⫽ 32 patients) Caucasian Hispanic African American Sex (n ⫽ 32 patients) Male Female Family history of retinoblastoma (n ⫽ 32 patients) Absent Present Affected eye (n ⫽ 34 eyes) Right Left Laterality (n ⫽ 32 patients) Unilateral Bilateral* History of trauma (n ⫽ 32 patients) Absent Present
No. (%) (n ⴝ 32 patients, 34 eyes) Feature 4 (3.5, 1.5–16) 26 (82) 4 (12) 2 (6) 19 (61) 13 (39)
31 (97) 1 (3) 18 (53) 16 (47) 27 (85) 5 (15) 27 (85) 5 (15)
*Of these 5 bilateral cases, 2 had bilateral diffuse retinoblastoma.
listed in Table 2. Eight eyes (24%) were referred with diagnoses other than retinoblastoma, including uveitis, Coats disease, and trauma. The anterior segment findings are listed in Table 3. Seventeen of 18 eyes (94%) in preverbal children were no fix or follow and 11 of 16 eyes (69%) in verbal children showed 20/200 or worse visual acuity. The most common anterior segment clinical findings included iris neovascularization (50%), tumor-induced pseudohypopyon (32%) or free-floating anterior chamber cells (32%), tumor seeds on the corneal endothelium (24%), and conjunctival injection (18%) (Fig 1). The tumor findings and related posterior segment features are listed in Table 4 (Fig 2). In all cases, the retinoblastoma was ill-defined without discrete tumor mass and the mean basal tumor diameter was 21 mm. Clinically, the tumors appeared as ill-defined thickening of the retina, but ultrasonographic measurement of the tumor apex (thickness) was a mean of 9 mm. This measurement included the tumor and underlying subretinal fluid down to the choroid. Tumor seeding into the vitreous (91%) or subretinal space (59%) and vitreous hemorrhage (24%) was common. The diagnostic testing results are listed in Table 5 and revealed lack of intraocular calcification by ultrasonography in 7 of 34 eyes (21%) and by computed tomography in 1 of 9 eyes (11%) (Fig 2). In those Table 2. Diffuse Infiltrating Retinoblastoma in 34 Eyes of 32 Patients: Referral Diagnosis Referring Diagnosis
No. (%) (n ⴝ 34 eyes)
Retinoblastoma Uveitis Coats disease Trauma Endophthalmitis Nonspecific retinal problem
26 (76) 3 (9) 1 (3) 1 (3) 0 (0) 3 (9)
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Table 3. Diffuse Infiltrating Retinoblastoma in 34 Eyes of 32 Patients: Visual Acuity and Anterior Segment Findings at Initial Examination
Visual acuity (n ⫽ 34 eyes) Verbal children (n ⫽ 16 eyes) 20/20–20/40 20/50–20/100 20/200–hand motions Light perception, no light perception Preverbal children (n ⫽ 18 eyes) Fix and follows No fix or follow Intraocular pressure (n ⫽ 34 eyes) Mean mmHg (median, range) IOPⱕ22 mmHg IOP⬎22 mmHg Ocular alignment (n ⫽ 32 patients) Orthophoria Exotropia Esotropia Anterior segment findings* (n ⫽ 34 eyes) Eyelid edema Conjunctiva edema Conjunctiva injection Cornea endothelium with tumor seeds Cornea stromal edema Cornea band keratopathy Anterior chamber free-floating tumor cells Anterior chamber tumor pseudohypopyon Anterior chamber hyphema Iris tumor seeds Iris neovascularization Iris heterochromia Lens cataract
No. (%) (n ⴝ 32 patients, 34 eyes)
2 (6) 3 (9) 5 (15) 6 (18) 1 (3) 17 (52) 25 (24, 10–51) 17 (50%) 17 (50%) 24 (76) 5 (15) 3 (9) 2 (6) 1 (3) 6 (18) 8 (24) 3 (9) 2 (6) 11 (32) 11 (32) 3 (9) 6 (18) 17 (50) 6 (18) 5 (15)
*Some patients had more than one finding.
eyes with evident calcification within tumor, the finding was minimal. All 34 eyes were managed with enucleation. Histopathology revealed retinoblastoma with poorly differentiated tumor (85%) and necrosis (88%) (Table 6). Iris neovascularization was found in 21 eyes (62%). Tumor invasion was found in the anterior chamber (47%), trabecular meshwork (44%), iris (41%), ciliary body (38%), choroid (12%), and postlaminar optic nerve (18%). Tumor invasion into the anterior chamber, optic nerve, choroid, or sclera was present in 22 eyes (single site in 9 patients, multiple sites in 13 patients) and absent in 12 eyes. On the basis of histopathologic findings, there were 16 patients who required chemotherapy for prevention of metastasis for a combination of reasons, including optic nerve invasion (n ⫽ 7), extraocular extension (n ⫽ 3), anterior chamber involvement (n ⫽ 9), lymphadenopathy with tumor (n ⫽ 1), and previous pars plana vitrectomy (n ⫽ 3). No patients developed further metastasis during a mean 47-month follow-up period.
Discussion There are several growth patterns of retinoblastoma, including exophytic, endophytic, mixed endophytic-exophytic,
Shields et al 䡠 Clinical Spectrum of Diffuse Infiltrating Retinoblastoma Pathology Department at the Institute of Ophthalmology in London showed this growth pattern. Most patients were older, and the tumor growth rate was suspected to be slow. In addition, there was a notable lack of tumor rosettes. Since these early histopathologic observations, little has been published on diffuse infiltrating retinoblastoma. Individual case reports and small case series have highlighted clinical features such as pseudohypopyon, hyphema, uveitis, and the unusual finding of heritable diffuse retinoblastoma.6 –13 Bhatnagar and Vine14 reviewed the published literature in 1991 and found only 34 cases, mostly case reports. They commented that computed tomography and ultrasonography were not helpful and that anterior chamber aspiration was often necessary to establish the diagnosis. Table 4. Diffuse Infiltrating Retinoblastoma in 34 Eyes of 32 Patients: Posterior Segment Findings at Initial Examination Feature Figure 1. Anterior segment findings in diffuse retinoblastoma demonstrating tumor pseudohypopyon in a 6-year-old patient (A), 16-year-old patient (B), 6-year-old patient (C), and 2-year-old patient (D). The referring diagnosis was uveitis (A, C) and retinoblastoma (B, D).
intraretinal, diffuse infiltrating, and spontaneous regression/ arrest (retinocytoma/retinoma).1,4,5 Intraretinal retinoblastoma refers to a small tumor that grows within the retina and does not produce subretinal fluid, subretinal seeds, or vitreous seeds.1 According to a recognized ophthalmic pathology textbook, diffuse infiltrating retinoblastoma is the least common growth pattern and often the most difficult to recognize clinically.4 Diffuse infiltrating retinoblastoma grows “diffusely within the retina without greatly thickening it.”4 There is no clear-cut definition or guideline for this tumor, but generally it is identified by flat infiltration of retinoblastoma within the retina without discrete nodularity. It can show a partially endophytic growth pattern, with tumor seeding into the vitreous, zonule, and anterior chamber. There are other cancers that can assume a flat growth pattern like pagetoid invasion of sebaceous carcinoma, morpheaform basal cell carcinoma, diffuse choroidal melanoma, and superficial spreading cutaneous melanoma. In 1958, Ashton suggested the term “diffuse infiltrating retinoblastoma” to describe the unusual nature of this flat neoplasm that did not produce a tumor mass within the retina.2 Several single case reports were recognized. In 1960, Schofield2 was the first to report on a series of eyes (n ⫽ 4) with diffuse retinoblastoma that were examined in the pathology laboratory at the Institute of Ophthalmology in London. Of these 4 eyes, the clinical features included tumor-induced pseudohypopyon (n ⫽ 4) and elevated intraocular pressure (n ⫽ 3), and all were later discovered to have retinoblastoma after aspiration of the anterior chamber. In 1971, Morgan3 described the pathologic features in 6 additional cases with illustrations of dramatically flat retinoblastoma on histopathology with tumor cells lining the retina, pars plana, pars plicata, and iris. He commented that only 10 of 720 eyes (1.4%) with retinoblastoma in the
Reese-Ellsworth Classification Group I Group II Group III Group IV Group V International Classification of Retinoblastoma Group A Group B Group C Group D Group E Location main tumor (n ⫽ 34 eyes) Superior Temporal Inferior Nasal Macula Basal diameter (mm) main tumor (n ⫽ 34 eyes) Mean (median, range) Thickness* (mm) main tumor (n ⫽ 34 eyes) Mean (median, range) Other posterior segment findings (n ⫽ 34 eyes) Vitreous tumor seeds† Vitreous tumor seeds extent 1 quadrant 2 quadrant 3 quadrant 4 quadrant Vitreous hemorrhage Subretinal fluid Subretinal tumor seeds Retinal telangiectasia NVE, NVD
No. (%) (n ⴝ 32 patients, 34 eyes) 0 (0) 0 (0) 0 (0) 0 (0) 34 (100)
0 (0) 0 (0) 0 (0) 6 (18) 28 (82) 3 (9) 6 (18) 11 (31) 7 (21) 7 (21)
21 (22, 10–40)
9 (8, 2–19)
31 (91) 0 (0) 1 (3) 1 (3) 29 (85) 8 (24) 24 (71) 20 (59) 1 (3) 1 (3)
NVD ⫽ neovascularization optic disc; NVE ⫽ neovascularization elsewhere. *Thickness was measured from the apex of the retinal tumor to the choroid and included retinal pathology and subretinal fluid. † In 1 patient with bilateral diffuse retinoblastoma, pars plana vitrectomy was performed bilaterally before referral.
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Figure 2. Clinical features, imaging, and gross pathology findings in diffuse retinoblastoma in a 5-year-old girl (A, B, C), 18-month-old girl (D, E, F), 4-year-old girl (G, H, I), and 2-year-old girl (J, K, L). Barely visible anterior chamber tumor cells (J) to frank pseudohypopyon (A) were visible. Ultrasonography revealed intraocular calcium (E) or lack of calcium (H), and computed tomography revealed calcium (L). Gross pathology showed diffusely minimally (C) or markedly (F, I) thickened retina from infiltrative retinoblastoma.
Our more contemporary series is the first large clinical series describing this unusual form of retinoblastoma in 34 additional eyes. Similar to Morgan’s3 findings from a pathology laboratory, we found 32 (2%) of 1507 patients with clinical evidence of retinoblastoma from the Ocular Oncology Service at Wills Eye Institute in Philadelphia displayed diffuse growth pattern, and older patient age was common (mean of 4 years). One of our intentions was to describe the spectrum of clinical features of this tumor. Salient features included poor visual acuity of 20/200 or worse in 69% (11/16 eyes of verbal children) and no fix or follow in 94% (17/18 eyes of preverbal children), iris neovascularization (50%), tumorinduced pseudohypopyon (32%), tumor seeds on iris (18%) or corneal endothelium (24%), and hyphema (9%). Less common features included eyelid edema (6%), conjunctival
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edema (3%), conjunctival injection (18%), corneal edema (9%), band keratopathy (6%), cataract (15%), and vitreous hemorrhage (24%). Nearly all eyes (91%) had visible vitreous tumor seeds, and most often the seeds involved all 4 quadrants (85%). Many of these features overlap findings with ocular inflammatory diseases or trauma; thus, there is difficulty in diagnosis. Ocular imaging can assist with differentiating retinoblastoma from uveitis and other causes of retinal detachment. Retinoblastoma classically displays intralesional calcification on ultrasonography, but many cases of diffuse retinoblastoma have had no demonstrable calcium with these studies.1,14,15 In one retrospective review of the literature, 4 of 28 eyes with diffuse retinoblastoma had calcification on histopathology.14 In our series, carefully performed ultrasonography in all 34 eyes showed retinal detachment (56%),
Shields et al 䡠 Clinical Spectrum of Diffuse Infiltrating Retinoblastoma vitreous opacification (76%), and presence of echoes consistent with calcium (79%). However, these echoes were often subtle, single echodensities in the vitreous and much less evident than those seen with classic nodular retinoblastoma. Computed tomography was available in 9 eyes, and disclosed intraocular calcification was observed in 89%. Histopathologically, some degree of dystrophic calcification was noted on routine sections within the tumor in 19 (56%) of the 34 eyes. Perhaps the improved resolution of ultrasound and computed tomography technology in more recent years, with attention to presence of calcium, has allowed improved detection. In every case, the diagnosis was made on clinical examination. In no case was fine-needle aspiration biopsy necessary to establish the diagnosis. Needle biopsy could be dangerous, because it could seed the tumor into the subconjunctival or orbital space and create a higher risk for metastatic disease.16,17 Pars plana vitrectomy had been performed before referral in 3 eyes of 2 patients, establishing the diagnosis histopathologically. All 3 eyes were enucleated, and both patients were treated with systemic chemotherapy for 6 months with no recurrence or metastasis at 4.2 and 10.8 years follow-up, respectively.18 In all cases, enucleation was necessary because of the advanced features of the malignancy. Histopathologically, most cases were poorly differentiated (85%). Necrosis was prominent (88%), and this factor may have contributed to the higher than expected presence of dystrophic calcification in our series. Tumor invasion was present in the anterior chamber (47%), trabecular meshwork (44%), iris (41%), ciliary body (38%), choroid (12%), and optic nerve deep to the lamina cribrosa (18%). Most of these are high-risk features that promote a greater risk for metastatic disease.19 Sixteen of the 32 patients required adjuvant chemotherapy to prevent metastasis; and no patient developed metastatic disease at a mean 4-year follow-up. Diffuse infiltrating retinoblastoma is a growth pattern found clinically in only 2% of eyes with retinoblastoma. This form of retinoblastoma often presents at an advanced stage and later than other clinical growth patterns, at a mean age of 4 years and up to 16 years in this series, compared with an overall Table 5. Diffuse Infiltrating Retinoblastoma in 34 Eyes of 32 Patients: Diagnostic Testing Diagnostic Test Ultrasonography (n ⫽ 34 eyes) Visible mass Calcification of tumor or seeds Retinal detachment Vitreous opacity Computed tomography (n ⫽ 9) Visible mass Calcification of tumor or seeds Retinal detachment Vitreous opacity Magnetic resonance imaging (n ⫽ 7) Visible mass Mass enhancement Retinal detachment Vitreous opacity
Table 6. Diffuse Infiltrating Retinoblastoma in 34 Eyes of 32 Patients: Histopathologic Findings Features Tumor differentiation Poorly differentiated Well differentiated Mixed Tumor findings Necrosis Rosettes Calcification dystrophic Invasion into ocular tissues Cornea Anterior chamber Trabecular meshwork Uvea Iris Ciliary body Choroid Zonule Vitreous Subretina Subretinal pigment epithelium Optic nerve Invasion to lamina cribrosa Invasion beyond lamina cribrosa Sclera Orbit* Iris neovascularization
No. (%) (n ⴝ 32 patients, 34 eyes) 29 (85) 3 (9) 2 (6) 30 (88) 13 (38) 19 (56) 1 (3) 16 (47) 15 (44) 14 (41) 13 (38) 4 (12) 7 (21) 28 (82) 19 (56) 17 (50) 11 (32) 6 (18) 1 (3) 1 (3) 21 (62)
*One patient with bilateral diffuse retinoblastoma who had pars plana vitrectomy performed before referral was found to have extraocular extension at the sclerotomy site.
mean age of approximately 18 months for the total patient population with retinoblastoma. Most patients present with advanced features of anterior segment invasion, glaucoma, and prelaminar or postlaminar optic nerve extension. Any child with signs of uveitis, hyphema, hypopyon, vitreous hemorrhage, or retinal detachment should be evaluated for retinoblastoma. Even if ocular imaging is negative for calcification, fundus evaluation by experienced examiners should be performed, and interventional procedures should be avoided until the diagnosis of retinoblastoma is clearly excluded.
No. (%) (n ⴝ 32 patients, 34 eyes) 32 (94) 27 (79) 19 (56) 26 (76) 6 (67) 8 (89) 2 (22) 1 (11) 6 (86) 4 (58) 3 (42) 0 (0)
References 1. Shields JA, Shields CL. Retinoblastoma: Introduction, Genetics, Clinical Features, Classification. In: Intraocular Tumors: An Atlas and Textbook. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:293–317. 2. Schofield PB. Diffuse infiltrating retinoblastoma. Br J Ophthalmol 1960;44:35– 41. 3. Morgan G. Diffuse infiltrating retinoblastoma. Br J Ophthalmol 1971;55:600 – 6. 4. McLean IW. Retinoblastomas, retinocytomas, and pseudoretinoblastomas. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and Textbook. 4th ed. vol. 2. Philadelphia, PA: Saunders; 1996; 1332– 438.
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Ophthalmology Volume 115, Number 12, December 2008 5. Shields CL, Mashayekhi A, Au AK, et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 2006;113:2276 – 80. 6. Nicholson D, Norton EW. Diffuse infiltrating retinoblastoma. Trans Am Ophthalmol Soc 1980;78:265– 89. 7. Shields JA, Shields CL, Eagle RC, Blair CJ. Spontaneous pseudohypopyon secondary to diffuse infiltrating retinoblastoma. Arch Ophthalmol 1988;106:1301–2. 8. Mansour AM, Greenwald MJ, O’Grady R. Diffuse infiltrating retinoblastoma. J Pediatr Ophthalmol Strabismus 1989;26: 152– 4. 9. Foster BS, Mukai S. Intraocular retinoblastoma presenting as ocular and orbital inflammation. Int Ophthalmol Clin 1996; 36:153– 60. 10. Shields JA, Shields CL, Materin M. Diffuse infiltrating retinoblastoma presenting as a spontaneous hyphema. J Pediatr Ophthalmol Strabismus 2000;37:311–2. 11. Kao LY. Diffuse infiltrating retinoblastoma: an inherited case. Retina 2000;20:217–9. 12. Materin MA, Shields CL, Shields JA, Eagle RC Jr. Diffuse infiltrating retinoblastoma simulating uveitis in a 7-year-old boy. Arch Ophthalmol 2000;118:442–3.
13. All-Ericsson C, Economou MA, Landau I, et al. Uveitis masquerade syndromes: diffuse retinoblastoma in an older child. Acta Ophthalmol Scand 2007;85:569 –70. 14. Bhatnagar R, Vine AK. Diffuse infiltrating retinoblastoma. Ophthalmology 1991;98:1657– 61. 15. Brisse HJ, Lumbroso L, Freneaux PC, et al. Sonographic, CT, and MR imaging findings in diffuse infiltrative retinoblastoma: report of two cases with histologic comparison. AJNR Am J Neuroradiol 2001;22:499 –504. 16. O’Hara BJ, Ehya H, Shields JA, et al. Fine needle aspiration biopsy in pediatric ophthalmic tumors and pseudotumors. Acta Cytol 1993;37:125–30. 17. Shields CL, Manquez ME, Ehya H, et al. Fine-needle aspiration biopsy of iris tumors in 100 consecutive cases: technique and complications. Ophthalmology 2006;113:2080 – 6. 18. Shields CL, Honavar S, Shields JA, et al. Vitrectomy in eyes with unsuspected retinoblastoma. Ophthalmology 2000;107: 2250 –5. 19. Honavar SG, Singh AD, Shields CL, et al. Postenucleation adjuvant therapy in high-risk retinoblastoma. Arch Ophthalmol 2002;120:923–31.
Footnotes and Financial Disclosures Originally received: April 23, 2008. Final revision: May 29, 2008. Accepted: July 10, 2008. Available online: October 29, 2008.
Manuscript no. 2008-506.
Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania. Supported by the Retina Research Foundation of the Retina Society in Cape Town, South Africa (CLS); the Scientific and Technical Research Council of the Turkish Republic (TUBITAK), Ankara, Turkey (ST); the Paul Kayser International Award of Merit in Retina Research, Houston, Texas (JAS); a donation from Michael, Bruce, and Ellen Ratner, New York, New York (JAS, CLS); the Mellon Charitable Giving from the Martha W. Rogers Charitable Trust, Philadelphia, Pennsylvania (CLS); the
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LuEsther Mertz Retina Research Foundation, New York, New York (CLS); and the Eye Tumor Research Foundation, Philadelphia, Pennsylvania (CLS, JAS). Financial Disclosure(s): The funders had no role in the design and conduct of the study; collection, analysis, and interpretation of the data; and preparation, review, or approval of the article. Carol L. Shields, MD, has had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. Correspondence: Carol L. Shields, MD, Ocular Oncology Service, Suite 1440, Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107. E-mail: carol.shields@ shieldsoncology.com.