From the Ocular Oncology Service, Wills Eye Institute, Philadelphia, Pennsylvania.
Support provided in part by the Retina Research Foundation of the Retina Society in Cape Town, South Africa (CLS) and the Eye Tumor Research Foundation, Philadelphia, Pennsylvania (CLS).
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Carol L. Shields, MD, Ocular Oncology Service, Suite 1440, Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107. E-mail: email@example.com
Retinoblastoma is an important, life-threatening intraocular malignancy of childhood.1 This malignancy generally shows aggressive features with rapid growth over several weeks to months, related subretinal fluid leading to retinal detachment, blindness, and occasional loss of the eye. The benign variant of retinoblastoma is known as retinocytoma/retinoma.1 This variant shows bland features with a stable, non-growing gray retinal mass, occasionally with intrinsic calcification and sometimes with associated surrounding retinal pigment epithelial alterations.2 This appearance resembles an irradiated or chemotherapy-treated regressed retinoblastoma.2 Viable retinoblastoma characteristically is composed of poorly differentiated, mitotically active basophilic cells, whereas retinocytoma/retinoma is composed primarily of cells showing photoreceptor differentiation, a sign of a well-differentiated tumor.3
In an analysis of 387 eyes enucleated for viable retinoblastoma and evaluated histopathologically at Wills Eye Institute, some degree of photoreceptor differentiation was found in 79 eyes (20%), and 19 of the 79 eyes with photoreceptor differentiation were classified as extensive or massive viable tumors.3 The presence of photoreceptor differentiation, generally at the viable tumor base, suggests an underlying retinocytoma/retinoma as precursor to viable retinoblastoma.3 In a clinical study of 17 patients with retinocytoma observed at the Oncology Service at Wills Eye Institute, retinocytoma was found to be remarkably stable because there was only 1 case (4%) to demonstrate clinically evident malignant transformation.2
Therapy for retinoblastoma has evolved over time and current conservative modalities employ the use of intravenous chemotherapy (chemoreduction) and adjuvant cryotherapy/thermotherapy or intra-arterial chemotherapy for tumor control.4 Local plaque radiotherapy is occasionally employed for small to medium localized tumors. It has been documented that low-grade retinoblastoma, such as cavitary retinoblastoma, shows poor response to chemoreduction.5 There have been no studies on the effects of chemoreduction on retinocytoma/retinoma because these tumors are usually managed with observation, not chemotherapy.6 There are instances where retinocytoma/retinoma might receive chemotherapy, particularly in the unusual situation where a child has active retinoblastoma in one eye and retinocytoma/retinoma in the other eye. We describe a child with advanced retinoblastoma in one eye that showed dramatic regression chemoreduction and retinocytoma in the fellow eye that showed no response to the same therapy.
A 30-month-old girl manifested esotropia in the left eye. There was no family history of retinoblastoma. Magnetic resonance imaging revealed bilateral retinal tumors with a small enhancing tumor in the right eye and a large, heterogeneous, enhancing mass with total retinal detachment in the left eye. The patient was referred for our consultation and treatment.
The visual acuity was fix and follow in the right eye and no fix or follow in the left eye. Intraocular pressures were normal. Leukocoria and iris neovascularization was found in the left eye. Fundus examination of the right eye showed three extramacular tumors 6 mm in diameter or less and 4 mm in thickness or less (Fig. A). There was no subretinal fluid or seeds in the right eye and this eye was classified as Group B by the International Classification of Retinoblastoma.7 Evaluation of the left eye showed a massive retinoblastoma measuring 24 × 24 × 14.4 mm with total retinal detachment and extensive vitreous and subretinal seeding, classified as Group E (Fig. 1B).7 B-scan ultrasonography confirmed partially calcified retinal tumors. These findings were consistent with the diagnosis of sporadic multifocal retinocytoma in the right eye and retinoblastoma in the left eye.
Figure. A 30-Month-Old Girl with Three Spontaneously Arrested Retinoblastomas in the Right Eye (A) (arrows) and Advanced Exophytic Retinoblastoma in the Left Eye (B) Showing No Response to Chemoreduction in the Right Eye (C) and Dramatic Regression in the Left Eye (D).
Six cycles of chemotherapy (vincristine [0.9 mg/m2], etoposide [90 mg/m2], and carboplatin [336 mg/m2]) were given monthly along with adjuvant cryotherapy and transpupillary thermotherapy. The left eye showed dramatic response with tumor reduction to 8 × 8 × 5 mm, whereas the right eye showed minimal tumor response (Figs. 1C and 1D). The lack of response in the right eye was strongly suggestive of a benign tumor-like retinocytoma/retinoma.
Retinocytoma/retinoma is considered a benign variant of retinoblastoma and accounts for approximately 3% to 5% of all retinoblastoma cases.2 This is considered a result of RB1 gene mutation that carries similar genetic implications as it does for retinoblastomas. More specifically, retinocytoma/retinoma show mutations in RB1 gene locus on chromosome 13q142.8 Dimaras et al. hypothesized that senescence induced by loss of alleles of RB1 gene caused genomic instability, thereby maintaining the arrested state of retinomas.9 Retinocytomas/retinomas also expressed high levels of p130, an effector of senescence, and they displayed low level genomic copy number changes resulting in non-proliferative tumor.9 However, further instability and mutations of the lesion caused progression to retinoblastoma.9 There remains confusion in the literature regarding terminology because some clinicians prefer the terms “spontaneously regressed retinoblastoma” or “spontaneously arrested retinoblastoma,” whereas others prefer “retinocytoma” or “retinoma.” These terms refer to this non-proliferative retinal precursor of retinoblastoma.3,9
Clinically, retinocytoma has been found to show a few characteristic features. An analysis of 24 retinocytomas in 17 patients from Wills Eye Hospital showed bilaterality in 3 cases (13%), family history of retinoblastoma in 3 (17%), and location in the macula in 7 (21%) and the extramacular region in 17 (79%) tumors.2 The clinical features included a translucent retinal mass in 21 of 24 tumors (88%), intrinsic calcification in 15 tumors (63%), and retinal pigment epithelial alterations in 13 tumors (54%).2 All tumors showed at least one of the features and the combination of all three features (translucent retinal mass, calcification, and retinal pigment epithelial alteration) was observed in 8 tumors (33%).2 Furthermore, 13 tumors (54%) showed zones of chorioretinal atrophy.2 In that small series, malignant transformation of retinocytoma to retinoblastoma was rare, with only 1 of 24 tumors (4%) showing malignant features.2
The International Classification of Retinoblastoma is a better predictor of chemoreduction success compared to the older Reese Ellsworth classification.7 Eyes with groups A, B, C, and D retinoblastoma showed success with chemoreduction in 100%, 93%, 90%, and 47%, respectively. In that analysis, retinocytoma/retinoma was not addressed because the tumors were generally observed. However, one study evaluated a relatively similar condition, cavitary retinoblastoma, a low-grade variant of retinoblastoma. This tumor is characterized by ophthalmoscopically visible cavitary spaces within the tumor and often without subretinal fluid or seeding, similar to retinocytoma/retinoma. The authors clearly showed that cavitary retinoblastoma shows minimal response to chemoreduction.5 This is important because it supports our observation that retinocytoma/retinoma show little to no response to chemoreduction.
Retinocytoma/retinoma is a benign variant of retinoblastoma, representing only 3% to 5% of all retinoblastomas and composed of well-differentiated cells.2 As demonstrated in this patient, retinocytoma/retinoma shows little to no response to chemoreduction.
- Shields JA, Shields CL. Intraocular Tumors: An Atlas and Textbook, 2nd ed. Philadelphia: Lippincott, Williams & Wilkins; 2008:293–317.
- Singh AD, Santos CM, Shields CL, Shields JA, Eagle RC Jr, . Observations on 17 patients with retinocytoma. Arch Ophthalmol. 2000;118:1991205.
- Eagle RC Jr, . High-risk features and tumor differentiation in retinoblastoma: a retrospective histopathologic study. Arch Pathol Lab Med. 2009;133:1203–1209.
- Shields CL, Mashayekhi A, Carter J, Shelil A, Meadows AT, Shields JA. Chemoreduction for retinoblastoma: analysis of tumor control and risks for recurrence in 457 tumors. Am J Ophthalmol. 2004;138:329–337. doi:10.1016/j.ajo.2004.04.032 [CrossRef]
- Mashayekhi A, Shields CL, Eagle RC, Shields JA. Cavitary changes in retinoblastoma: relationship to chemoresistance. Ophthalmology. 2005;112:1145–1150. doi:10.1016/j.ophtha.2005.01.041 [CrossRef]
- Naseripour M, Falavarjani KG, Akbarzadeh S. Retinocytoma associated with bilateral retinoblastoma. Indian J Ophthalmol. 2010;58:155–156. doi:10.4103/0301-4738.60094 [CrossRef]
- Shields CL, Mashayekhi A, Au AK, et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology. 2006;113:2276–2280. doi:10.1016/j.ophtha.2006.06.018 [CrossRef]
- Gallie BL, Ellsworth RM, Abramson DH, Phillips RA. Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation?Br J Cancer. 1982;45:513–521.
- Dimaras H, Khetan V, Halliday W, et al. Loss of RB1 induces nonproliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma. Hum Mol Genet. 2008;17:1363–1372. doi:10.1093/hmg/ddn024 [CrossRef]