Retinoblastoma (Rb) is the most common primary intraocular malignancy in children and is second in total worldwide prevalence to uveal melanoma. Incidence rates of Rb and survival rates among patients with Rb vary substantially by country.¹ In their epidemiological registry-based study, Virgili and colleagues² address the survival and health care burden of children with Rb in Europe from 2000 to 2013. They report that the incidence of Rb within most European countries remained stable at 4 cases per 1 million person-years aged 0 to 14, with an expected overall 5-year survival rate of 97.8%. Cancer registries are extensively used to provide valuable incidence and prevalence data. However, in tumors like Rb, registry data may be particularly subject to bias. Rb is a tumor that may be hereditable and multicentric, and it may not always be confirmed histologically. In addition, Rb is treated with a variety of treatment approaches, all of which make it difficult to systematically capture all data in the epidemiological registry. For example, in this European study, only 28.4% of cases where laterality was reported were noted to be bilateral, which is lower than the expected rate (40%). This may be due in part to the limitations of the registry. It is likely that some patients who initially were reported as unilateral but later developed Rb in the fellow eye did not have their laterality status updated.

Another bias of the registry data can be exemplified with the data from Bulgaria, where the 5-year Rb survival rate appears to be less than 70%, compared with the 97.8% survival rate observed in Europe overall. While it is possible that the actual survival rate is lower in Bulgaria, the lower rate could be related to ascertainment bias. However, lower survival rates are generally observed in Eastern European countries.

An important issue related to worse outcomes in the study is the impact of migration on the overall results, and the authors briefly mention treatment migration in their discussion. Migration or referral from 1 European country to another could be associated with the registry statistics if a patient is counted twice or is counted in the country to which they were referred. Late referral of Rb cases from resource-limited countries without Rb centers, such as some areas in Africa, to centers of excellence in central Europe could also affect observed survival rates. Finally, the methodology did not address patients鈥� ethnicity and nationality of origin, which might be important because of the different waves of migration from the Middle East and North Africa into Europe. If children of migrants arrived at a European country with advanced Rb, these patients might be counted as from that European country, altering the interpretation of incidence rates and outcomes for the country in which the child was treated. Statistics from the 2024 World Migration Report³ show that Germany, France, Poland, and Turkey were the European countries with highest influx of immigrants. In Virgili and colleagues鈥� study,² the highest numbers of Rb cases were in Germany (n鈥�=鈥�550) and France (n鈥�=鈥�695).

Another important reporting issue relates to the reporting of secondary tumors. In this study, trilateral retinoblastoma was considered a second malignancy. However, in this era of genomic testing, most intracranial primitive tumors represent a multicentric tumor rather than a secondary malignancy. Another finding of this European registry study was confirmation of higher secondary malignancy risks for hematological malignancies and tumors of head and neck (all rhabdomyosarcomas), brain, and bone and soft tissues. These observations demonstrate the value of large registries, which can identify risks that otherwise might not be accounted for in single-institution studies. This study also showed a relatively low incidence of solid tumors, and this is probably associated with discontinuation of the use of external beam radiation therapy. Because this registry has relatively short follow-up, one would not expect to be able to assess the incidence of secondary malignancies, which usually appear later in life. In the introduction, Virgili and colleagues² state that 鈥淚n high-income countries, death from retinoblastoma is rare, whereas in low-income countries, estimated 3-year survival is just under 60%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.鈥� Two different studies of middle-income countries (MIC) and low-income countries (LIC)^1,4 suggest that treatments for patients with Rb are not appropriately resourced. In a 2020 assessment of capacity to treat retinoblastoma in the Middle East and North Africa, Burges and colleagues⁴ concluded that there were common themes related to the treatment of Rb in LIC and MIC, including decentralization of care, limited resources, and lack of multidisciplinary care. They also proposed that resource disparities merit targeted intervention in these regions (ie, the Middle East, North Africa, and West Asia) to improve the management of Rb. Overall, LIC and, to some extent, MIC have worse outcomes than high-income countries not only because of delayed diagnosis, but also predominantly for the lack of adequate health care systems. Recent multicenter studies have tried to address the factors associated with discrepant survival outcomes of Rb worldwide. In their international, multicenter, registry-based analysis, Tomar and colleagues¹ focused their attention on management outcomes by country and found that lower national income levels were associated with higher rates of metastasis-related mortality, local treatment failure, and lower globe salvage. Ideally, countries should be able to offer adequate treatment and follow-up, genetic counseling, social services, and a multidisciplinary approach (composed of ophthalmologists, oncologists, pathologists, geneticists, and radiation oncologists) for the care of children with Rb.^4,5 One additional finding in this study was the presence of secondary acute myeloid leukemia, confirming what was originally reported by Gombos and colleagues.⁶

In summary, Virgili and colleagues² reported a stable incidence of Rb over a 10-year period for most of Europe. They found an encouraging expected overall survival rate of 97.8%. An important additional contribution from this study is data on the incidence of secondary malignancies in children with Rb. The study鈥檚 limitations are intrinsic to the methodology used, which failed to capture all the nuances of a tumor like Rb, and because the authors did not include all European countries, the data may not be representative of the entire region.

Corresponding Author: Patricia Ch茅vez-Barrios, MD, Department of Pathology and Genomic Medicine, Houston Methodist Hospital, 6565 Fannin St, M227, Houston, TX 77030 (pchevez-barrios@houstonmethodist.org).

Published Online: October 10, 2024. doi:10.1001/jamaophthalmol.2024.4268

Conflict of Interest Disclosures: None reported.