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Editorial

International Classification and Management of Retinoblastoma

etinoblastoma is the most common primary intraocular malignancy in children.1 It represents approximately 4 percent of all malignancies in children and one percent of human cancers.2 Retinoblastoma gene was the first cancer gene cloned in 1986.3 It is estimated that 250 to 350 new cases of retinoblastoma are diagnosed in the United States each year and 5,000 to 8,000 cases are found worldwide. On an average, 25 cases are diagnosed in Saudi Arabia each year. The successful management of retinoblastoma is due to the general development of ophthalmic techniques in medicine, but still complex, variable and includes enucleation and conservative (non-enucleation) methods. The most current conservative method is intravenous chemotherapy as chemoreduction to reduce the retinoblastoma lesions, followed by focal treatment modalities such as cryotherapy, laser photocoagulation, transpuppillary thermotherapy (TTT), chemothermotherapy and custom design plaque radiotherapy.4,5 External beam radiotherapy may not be avoidable in some cases, but is used less often than last decades and that because of the high success of the new methods and the external beam radiotherapy local complications. The high successes of the new modalities in the management of retinoblastoma showed clinicians the difficulties in applying the commonly used Reese-Ellsworth classification for conservative treatment of retinoblastoma. Reese and Ellsworth presented their classification at the 67th annual meeting of the American Academy of Ophthalmology.6 Their goal was to have guidelines to predict the success of the external beam radiotherapy in the retinoblastoma management. This classification has remained widely used for the last four decades, it is difficult to recall the 5 groups in details and the likelihood of globe salvage may not be comparable to the success rate with new modalities. Several methods of classification have been developed for intraocular retinoblastoma, and the more recent is the International Classification of Retinoblastoma (ICRB)7, 8 (Table 1). The current ICRB is very useful in guiding the treating clinician to choose the most appropriate treatment methods and might assist the predication of the chemoreduction and focal treatment meth-

ods success for the intraocular retinoblastoma cases.9 Treatment tailoring could be made to manage each group by different strategies. In general, eyes classified as group A are managed by cryotherapy, laser photocoagulation or transpuppillary thermotherapy (TTT). Eyes classified as group B are managed by chemothermotherapy, brachytherapy or cryotherapy. Eyes classified as group C are managed by chemoreduction, chemothermotherapy, cryotherapy or brachytherapy. By using the ICRB, the bilateral cases of group D or E are managed by chemoreduction, thermotherapy or low dose of external beam radiotherapy, but group E often require enucleation.10 On the basis of ICRB, the chemoreduction and focal treatment methods success achieved in 100 percent of group A, 93 percent in group B, 90 percent in group C, and 47 percent in group D eyes.9 The ICRB is very simple, can be easily remembered and has high predictabilities in the treatment success to avoid enucleation and external beam radiotherapy. The ICRB is designed after the high success rate of the new treatment methods
Table. International Classification of Retinoblastoma Group A B Features Small tumor: 3 mm Large tumor: >3 mm Macular: 3 mm to foveola Juxtapapillary: 3 mm to disc Subretinal fluid: 3 mm from the margin Focal seeds Subretinal seeds: 3 mm Vitreous seeds: 3 mm Both subretinal and vitreous seeds: 3 mm Diffused seeds Subretinal seeds: >3 mm Vitreous seeds: >3 mm Both subretinal and vitreous seeds: >3 mm Extensive retinoblastoma occupying more than 50% or neovascular glaucoma or opagque media from hemorrhage in anterior chamber, vitreous or subretinal space

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that may or may not include chemotherapy. Eyes with confined tumor (group A and B) are successfully treated with chemoreduction and focal treatment methods regardless of the size, number, or location of the retinoblastoma lesions, and have a success rate of 100 percent for group A and 93 percent for group B. Such favorable results will not be predictable by applying the Reese and Ellsworth classification.7 Careful and diligent follow-up is the mainstay to ensure the success. The main problem of treatment with chemoreduction is the recurrence of subretinal or vitreous seeds and may require cryotherapy, thermotherapy, brachytherapy, external beam radiotherapy, or enucleation. Twenty four percent of young patients might develop new lesion during or after the chemoreduction, and it is commonly seen in patients who were presented as infants and have a positive family history of retinoblastoma.11 Currently, the Childrens Oncology Group (COG) is evaluating the chemoreduction for the intraocular retinoblastoma as well as chemotherapy for high-risk retinoblastoma cases.10 Abdallah in this issue of the Saudi Journal of Ophthalmology demonstrates the recent decreasing frequency of enucleation for intraocular retinoblastoma in Upper Egypt.12 Reese-Ellsworth classification is used in this study; his aim was to avoid the external beam radiotherapy and enucleation. Chemotherapy and the available focal treatment methods was the mainstay of the treatment. It will be very difficult to predict success rate by using the Reese-Ellsworth classification, the study outcome showed that 14 of the total 30 eyes (46.7%) could not be salvaged with chemoreduction and focal treatment methods and required externalbeam radiotherapy, enucleation or both. In summary, the retinoblastoma cases are now classified into groups A, B, C, D, and E, based on the tumor size, location and absence or presence of subretinal or vitreous seeds. The new classification will be the most appropriate to be used with the new modalities of the management of the intraocular retinoblastoma cases. Retinoblastoma continues to be a challenge diagnostically at early stages and therapeutically by expert clinicians in the center of excellence for retinoblastoma management.

2. Shields JA, Shields CL. Retinoblastoma. In: Shields JA, Shields CL, editors. Atlas of intraocular tumors. Philadelphia: Lippincott Williams; 1999.pp.207-232. 3. Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986; 323:543646. 4. Sheilds CL, DePotter, Himmelstein B, et al. Chemoreduction in the initial management of intraocular retinoblastoma. Arch Opthalmol 1996;114:13301338. 5. Murphree AL, Villablanca JG, Deegan WF III, et al. Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol 1996;114:1348-1456. 6. Reese AB, Ellsworth RM. Evalution and current concept in retinoblastoma therapy. Trans Am Acad Ophthlalmol Otolaryngo 1963;67:164-172. 7. Sheilds CL, Mashayekhi A, Demirci H, et al. A practical approach to management of retinoblastoma. Arch ophthalmol 2004;122:729-735. 8. Murphree AL. Intraocular retinoblastoma: the case for new group classification. Ophthalmol Clin North Am 2005;200(viii):41-53. 9. Sheilds CL, Au Ak, Czyz C, et al. The International Classification of Retinoblastoma (ICBR) predicts chemoredction success. Presented at the International Society of Ocular Oncology; September 1-5, 2005; Whistler, Canada and American Academy of Ophthalmology October 14-16, 2005. 10. Sheilds CL, Shields JA. Basic understanding of current classification and management of retinoblastoma. Curr Opin Ophthalmol 2006;17:228-234. 11. Abramson DH, Frank CM, Dunkel IJ. A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma. Ophthalmology 1999;106:1947-1950. 12. Abdallah A M. Recent Decreasing Frequency of Enucleation for Intraocular Retinoblastoma in Upper Egypt. Saudi J Ophthalmol 2006;20:168-175.

REFERENCES
1. Shields JA, Shields CL. Management and prognosis of retinoblastoma. In: Intraocular tumors: a text and atlas. Philadelphia: WB Saunders; 1992.pp.377-392.

SALEH AL-MESFER, MD
Senior Clinical Consultant Chief, Pediatric Ophthalmology Department King Khaled Eye Specialist Hospital PO Box 7191, Riyadh 11462 Kingdom of Saudi Arabia

Saudi Journal of Ophthalmology, Volume 20, No. 3, July September 2006