Managing and tracking the worldwide burden of retinoblastoma

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A new study from investigators in Romania examined the incidence rates of retinoblastoma, the need for enhanced screening, treatment options, and long-term prognosis for children with this inherited disease in northeastern Romania. Enhanced screening is critical because of the advanced stage of retinoblastoma at presentation.¹ The investigators, led by first author Vlad Constantin Donica, PhD, are from the Department of Ophthalmology, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, and the Department of Ophthalmology, Sf. Spiridon Emergency County Hospital, both in Iasi, Romania.

Clinical presentation

Based on the stage of the disease, the clinical signs can range from small (under 2 mm) intraocular tumors, which look like transparent retinal spots, to larger tumors with vessels and white calcified lesions; a large tumor can occupy the entire vitreous cavity and touch the lens, investigators explained.

Leukocoria, which can be present with all forms of retinoblastoma and is the most common sign, can vary from a subtle appearance to a completely white pupil with large tumors. Strabismus is the next most common sign, and more advanced forms can have changes in the iris color and neovascularization, an enlarged cornea and enlarged globe due to increased intraocular pressure, and proptosis with delayed presentation.²

Delayed diagnoses

The investigators explained that retinoblastoma, the most common pediatric ocular tumor, lacks both proper genetic testing and case registration, resulting in advanced disease stages at patients’ initial presentation.

Donica and colleagues cited results of previous studies that showed that countries in Eastern Europe had the fewest data from patients with retinoblastoma compared with Asia, Africa, Latin America, and North America. Specifically, the Automated Childhood Cancer Information System analyzed 60 pediatric oncology centers between 1978 and 1997 and identified 1995 cases of retinoblastoma from all across Europe. In Eastern Europe, only Belarus, Estonia, Slovakia, and Hungary were among the analyzed countries.³

A study⁴ that was part of the Surveillance of Rare Cancers in Europe assessed the incidence, prevalence, and survival rate of the main embryonal cancers in Europe and found that retinoblastoma was third in incidence and second in survival rate. From 1995 to 2002, analysis of data from the EU showed that during that period, only Poland submitted data. A 2021 report on European incidence of retinoblastoma presented incomplete data from several eastern European countries, including Romania, and reported 8 newly identified cases in 2017.⁵ “The lack of proper data-gathering highlights the importance of reviewing the current status of patients that were diagnosed with retinoblastoma in developing countries,” Donica and colleagues commented.

Retrospective analysis

The study under discussion is a 10-year retrospective analysis of patients diagnosed with retinoblastoma between 2014 and 2024 in Sf. Spiridon Hospital.

The authors identified 10 cases (7 boys, 3 girls; average patient age, 25.9 months), 9 of which had a unilateral tumor and 1 with bilateral tumors. All patients were diagnosed at presentation with clinical stage E, defined as a large tumor touching the lens, with increased intraocular pressure and an enlarged globe (Table).

“Enucleation with successful tumor excision was performed in 6 of 7 cases. Two patients underwent conservative treatment, and one patient was unable to be reached after the diagnosis,” the investigators reported.

The 6 children who underwent successful enucleation had no tumor recurrences. They received a successful ocular prosthesis and, if required, cosmetic reconstruction. The patient with unsuccessful tumor excision had bilateral retinoblastoma that had a delayed initial presentation/diagnosis. Despite aggressive intravenous treatment and enucleation, the tumor recurred with systemic metastasis, and the patient died.

Regarding conservative treatment, 1 patient has had a history of unilateral retinoblastoma for 7 years and underwent 2 cycles of intra-arterial chemotherapy, 13 intravitreal injections, 12 sessions of cryotherapy, 8 sessions of thermotherapy, laser treatment, and cerclage in the first 4 years after the initial diagnosis. An artificial lens was implanted after lensectomy. The patient continues to be followed and treated for amblyopia. The vision currently is 20/25. The tumor remained stable.

The second patient treated conservatively underwent 1 cycle of intra-arterial chemotherapy and intravitreal injections with a favorable response. In this study, based on the American Joint Committee on Cancer, 42.85% of tumors were classified as grade G2, and 57.15% as G3. The optic disc was invaded in 71.42% of cases, with further nerve invasion in 40%. Uveal invasion was present in 57.14% of cases.

Donica and associates commented, “Our 10-year analysis of 10 cases averaged 1 case of newly identified retinoblastoma annually. These data suggest that the incidence of retinoblastoma in our region has a rate of 1:28,554, while cited data report 1:15,000 to 1:20,000 per child birth. Our lower incidence could result from the presentation of these children to other centers across the country. Therefore, the need for a unified registry for following and understanding the different varieties in pediatric cancers has never been greater.”

Early diagnosis

High-resolution ultrasound can identify lesions exceeding 2 mm and is superior to fetal magnetic resonance imaging, which is more useful for identifying extraocular tumor extension.⁶ Early prenatal screening can be performed invasively and noninvasively, with the latter using fetal cell-free DNA from a maternal blood sample to search for new/inherited mutations. Invasive methods include amniocentesis or chorionic villi sampling.⁷

Future parents with a history of retinoblastoma can undergo genetic testing during in vitro fertilization, providing them with information on the Rb1 mutation status before embryonic implantation.^7,8

Incipient retinoblastoma detection with early delivery provides a better chance of successful treatment with possible ocular salvage, while term deliveries allow more time for tumoral growth and spread, compromising treatment effectiveness.^9,10 “This more than justifies the necessity of prenatal genetic screening in patients with a risk for developing retinoblastoma,” the investigators said.

Despite universally available ultrasonography and prenatal screening using invasive and noninvasive methods in Romania, no study patients were diagnosed with retinoblastoma using prenatal ultrasound, they pointed out.

Optical coherence tomography (OCT) of the posterior segment is another noninvasive option.^11,12 While OCT is routinely used to diagnose many ophthalmologic pathologies in their clinic, the lack of handheld devices for neonatal screening resulted in delayed diagnosis with advanced disease at presentation, they said.

The authors emphasized the need for registries in developing countries to best manage and monitor the incidence of retinoblastoma. “In our study, all children had an initial presentation with disease stage E, which highlights the need to intensify screening measures in infants to diagnose this disease earlier. Therefore, the lack of proper genetic testing makes us unable to report how many tumors had germline or developed somatic mutations and to provide patients adequate information regarding the risk of their offspring inheriting Rb1 gene mutations. Unfortunately, enucleation remains the primary treatment method for retinoblastoma in Romania, despite access to conservative eye-saving treatment measures.”

References

1. Donica VC, Costea CF, Sandu CA, Pavel IA, Bogdănici CM. Prevalence and management of retinoblastoma. a 10-year retrospective analysis from North-Eastern Romania.Chirurgia (Bucur).2025;120:294-302.DOI: 10.21614/chirurgia.3109

2. Dimaras H, Corson TW, Cobrinik D, et al. Retinoblastoma. Nat Rev Dis Primers. 2015;1:15021.

3. MacCarthy A, Draper GJ, Steliarova-Foucher E, Kingston JE. Retinoblastoma incidence and survival in European children (1978–1997). Report from the Automated Childhood Cancer Information System project. Eur J Cancer. 2006; 42:2092-102.

4. Gatta G, Ferrari A, Stiller CA, et al. Embryonal cancers in Europe. Eur J Cancer. 2012;48:1425-33.

5. Stacey AW, Bowman R, Foster A, et al. Incidence of retinoblastoma has increased: results from 40 European countries. Ophthalmology. 2021;128:1369-71.

6. Paquette L, Miller D, Jackson H, et al. In utero detection of retinoblastoma with fetal magnetic resonance and ultrasound: initial experience. AJP Rep. 2012;2:55-62.

7. Rodriguez A, Kelley C, Patel A, Ramasubramanian A. Prenatal diagnosis of retinoblastomas: a scoping review. Int J Gen Med. 2023;16:1101-10.

8. Gerrish A, Bowns B, Mashayamombe-Wolfgarten C, et al. Non-Invasive Prenatal Diagnosis of Retinoblastoma Inheritance by Combined Targeted Sequencing Strategies. J Clin Med. 2020;9:3517.

9. Soliman SE, Dimaras H, Khetan V, et al. Prenatal versus postnatal screening for familial retinoblastoma. Ophthalmology. 2016; 123:2610-2617

10. Toi A, Sutherland J, Gallie B, Gardiner J, Sermer M. Evaluation of the fetus at risk for retinoblastoma: what is the role of prenatal ultrasound? Ultrasound Med Biol. 2003;29:S137.

11. Shields CL, Shields JA. Diagnosis and management of retinoblastoma. Cancer Control. 2004;11:317-27.

12. Shields C, Manalac J, Das C, Saktanasate J, Shields J. Review of spectral domain-enhanced depth imaging optical coherence tomography of tumours of the retina and retinal pigment epithelium in children and adults. Indian J Ophthalmol. 2015;63:128-32.