Screening for Pineal Trilateral Retinoblastoma Revisited a Meta-Analysis

Screening for Pineal Trilateral Retinoblastoma Revisited A Meta-analysis

Marcus C. de Jong, MD, PhD,1 Wijnanda A. Kors, MD,2 Annette C. Moll, MD, PhD,3 Pim de Graaf, MD, PhD,1 Jonas A. Castelijns, MD, PhD,1 Robin W. Jansen, MD,1 Brenda Gallie, MD,4,5 Sameh E. Soliman, MD,4,6 Furqan Shaikh, MD,7 Helen Dimaras, PhD,4,5,8,9 Tero T. Kivelä, MD10

Topic: To determine the age up to which children are at risk of trilateral retinoblastoma (TRb) developing, whether its onset is linked to the age at which intraocular retinoblastomas develop, and the lead time from a detectable pineal TRb to symptoms. Clinical relevance: Approximately 45% of patients with retinoblastomadthose with a germline RB1 pathogenic variantdare at risk of pineal TRb developing. Early detection and treatment are essential for survival. Current evidence is unclear regarding the usefulness of screening for pineal TRb and, if useful, the age up to which screening should be continued. Methods: We conducted a study according to the Meta-analysis of Observational Studies in Epidemiology guidelines for reporting meta-analyses of observational studies. We searched PubMed and Embase between January 1, 1966, and February 27, 2019, for published literature. We considered articles reporting patients with TRb with survival and follow-up data. Inclusion of articles was performed separately and independently by 2 authors, and 2 authors also independently extracted the relevant data. They resolved discrepancies by consensus. Results: One hundred thirty-eight patients with pineal TRb were included. Of 22 asymptomatic patients, 21 (95%) were diagnosed before the age of 40 months (median, 16 months; interquartile range, 9e29 months). Age at diagnosis of pineal TRb in patients diagnosed with retinoblastoma at 6 months or younger versus older than 6 months were comparable (P 0.44), suggesting independence between the ages at diagnosis of intraocular retinoblastoma and pineal TRb.¼ The laterality of intraocular retinoblastoma and its treatment were not associated with the age at which pineal TRb was diagnosed. The lead time from asymptomatic to symptomatic pineal TRb was approximately 1 year. By performing a screening magnetic resonance imaging scan every 6 months after the diagnosis of heritable retinoblastoma (median age, 6 months) until 36 months of age, at least 311 and 776 scans would be required to detect 1 case of asymptomatic pineal TRb and to save a single life, respectively. Conclusions: Patients with retinoblastoma are at risk of pineal TRb developing for a shorter period than previously assumed, and the age at diagnosis of pineal TRb is independent of the age at diagnosis of retinoblastoma. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) level of evidence for these conclusions remains low. Ophthalmology 2020;127:601-607 ª 2019 by the American Academy of Ophthalmology

Supplemental material available at www.aaojournal.org.

Trilateral retinoblastoma (TRb) refers to retinoblastoma retinoblastoma (bilateral and unilateral tumors with family presenting with a midline intracranial neoplasm resembling history or a germline RB1 pathogenic variant) and 2.9% (95% an embryonal tumor of the central nervous system. Patients conﬁdence interval, 1.9%e4.2%) of patients with bilateral with TRbdof whom three quarters have pineal TRb retinoblastoma.1 Because 45% of all retinoblastomas are (pineoblastoma) and one quarter have suprasellar or para- heritable2 and approximately 8000 new patients are sellar TRbdare carriers of a germline RB1 pathogenic expected globally each year,3 should all of them survive, variant who typically also will have bilateral intraocular TRb is predicted to affect approximately 125 children retinoblastoma. Trilateral retinoblastoma is an important annually, in 90 of whom pineal TRb would develop. cause of death among patients with heritable retinoblastoma. Unlike nonpineal TRbs, pineal TRbs often are diagnosed The incidence of pineal TRb, according to our recent after the intraocular tumor is diagnosed (metachronous).4 The systematic review and meta-analysis, is 3.2% (95% conﬁ- often metachronous diagnosis of pineal TRb raises the dence interval, 1.4%e5.6%) of all patients with heritable question whether, and at which frequency, neuroradiologic

ª 2019 by the American Academy of Ophthalmology https://doi.org/10.1016/j.ophtha.2019.10.040 601 Published by Elsevier Inc. ISSN 0161-6420/19 Ophthalmology Volume 127, Number 5, May 2020 screening should be adopted for a child with a germline RB1 Overall Level of Evidence pathogenic variant. In practice, most centers follow the We graded the level of evidence of the 2 research questions stated recommendation to perform brain magnetic resonance 13 in the introduction according to the GRADE system. imaging (MRI) for children with retinoblastoma at diagnosis.4e8 However, some centers repeat the MRI for children up to 5 years of age,9 although the benefit from this Statistical Analysis practice is unclear.10 Whether screening for pineal TRb is useful is unclear even today. The objective of this study We used IBM SPSS Statistics (Armonk, NY) software version 22. The cumulative frequency of TRb by age at diagnosis and by the was to contribute to solving this problem by answering 2 time from intraocular retinoblastoma was plotted. The previously unanswered questions: (1) Until which age are ManneWhitney U test was used to compare subgroups. Spear- patients with heritable retinoblastoma at risk of pineal TRb man’s r was used to calculate a correlation between 2 continuous developing? and (2) Does pineal TRb develop earlier if a variables. P values less than 0.05 were considered statistically patient is diagnosed with retinoblastoma at an early age significant. All tests were 2 sided. For the main analyses, data of ( 6 months)? patients diagnosed in 1995 or later were included (see prior pub- lications14,15). We consider that this period, beginning with the introduction of chemotherapy to the routine management of Methods retinoblastoma, most accurately corresponds to management today in terms of diagnostic methods and treatment for both Search Strategy, Study Selection, and Data intraocular retinoblastoma and TRb. We used data from patients diagnosed before 1995 to check the robustness of our analyses in Extraction the event that sample sizes were small. We performed this study according to the Enhancing the Quality and Transparency of Health Research reporting guidelines, including the Meta-analysis of Observational Studies in Epidemi- Results ology.11 This study adhered to the tenets of the Declaration of Helsinki. The ethics committee at VU Medisch Centrum Included Studies and Patients approved this study with a waiver of informed consent. We updated our literature search of the English, Dutch, and Our updated search resulted in 185 PubMed and 336 Embase hits German literature for patients with TRb as performed for the 2014 (Appendix B, available at www.aaojournal.org). After excluding systematic review and meta-analysis by de Jong et al,4 with a new 52 duplicates, we reviewed 469 titles and abstracts for eligibility search (PubMed and Embase) performed on February 27, 2019 and excluded 451 articles. Eighteen articles were eligible, and we 10 (performed by M.C.d.J. with 9 years of experience in conducting reviewed their full text. One article included only previously 16e21 systematic reviews and meta-analyses; Appendix A, available at published patients. Six articles did not provide the age at 22,23 www.aaojournal.org). To ensure sensitivity, the search strategy diagnosis of TRb, 2 articles reported on patients with a TRb 24e26 included only terms describing the target disease (Appendix A). but without an intraocular tumor, and 3 articles did not Two authors (M.C.d.J. and A.C.M.) independently reviewed all report on patients with TRb at all and were excluded. The 6 27e32 articles for inclusion, and 2 authors (M.C.d.J. and W.A.K.) remaining articles provided 15 new patients. Together with 4 independently extracted data from the included articles. We 174 patients from our earlier systematic review, we compiled data extracted all data as described previously4 to update our entire from 189 patients with TRb (Appendix C, available at TRb database. If TRb was diagnosed within 3 months of www.aaojournal.org). diagnosis of intraocular tumor, we considered the tumors Of all patients, 138 (73%) had a pineal TRb; 42 (22%) had a synchronous. Patients were included if they were identifiable as suprasellar, parasellar, or ventricular TRb; and 3 (2%) had both a 5,33 unique and if at least the age at which the TRb was diagnosed pineal and a nonpineal TRb. In the remaining patients (3%), the was available. Overlap between patients was identified using all location of the TRb was unspecified. Of the 183 patients with a available data in included studies (such as age at diagnosis, TRb in a known location, 73 (40%) were diagnosed in 1995 or gender, and hospital where patient was treated); if uncertainty later, of whom 50 (68%) had a pineal TRb, 21 (29%) had a remained, the most recently published case was excluded. nonpineal TRb, and 2 (3%) had both tumors; 37 (51%) of them Discrepancies were resolved by consensus. were synchronous, 28 (38%) were metachronous, 1 was Authors of articles published in 1995 or earlier were contacted diagnosed before the intraocular tumor, and in 7 (11%) patients, via e-mail (in October 2017 and February 2019) for additional the sequence was unspecified. Restricting to pineal TRb, of the information relevant to the research questions (whether there was a 50 patients diagnosed in 1995 or later, 18 (36%) had screening program for TRb in place, whether TRb was detected synchronous tumors, 26 (52%) had metachronous tumors, and in during screening of after development of symptoms, and whether 6 (12%) patients, this was unspecified. and when previous scan showing negative results was performed); however, none responded. Risk of Bias and Study Quality Risk of Bias and Study Quality Of the 96 included articles, 74 (71%) did not fulfill the first cri- terion in the quality checklist (Appendix D, available at Risk of bias and methodologic quality of each article were assessed www.aaojournal.org), indicating that they likely reported patients with a checklist proposed by Murad et al.12 Checklist items 5 and 6 who were interesting and did not necessarily present the entire were not included because they are relevant only to adverse drug experience the authors had with TRb. In 17 studies (18%), 1 or events. Two authors (M.C.d.J. and R.W.J.) independently scored more false-positive diagnoses could not be entirely ruled out all included articles according to the checklist. Discrepancies (e.g., patient 151 in Appendix C received no follow-up and had a were resolved by consensus. small presumed cystic pineal TRb of 11 mm).

602 de Jong et al Screening for Trilateral Retinoblastoma

100% 60

50 80%

60%

≈12 months 30

40% 20 Cumulative frequency Cumulative

20% 10 Clinical Clinical presentation presentation Asymptomatic Asymptomatic Symptomatic (months) retinoblastoma trilateral pineal of diagnosis at Age Symptomatic 0 0% 010203040 01224364860 Age at diagnosis of pineal trilateral retinoblastoma (months) Age at diagnosis of intraocular retinoblastoma (months) Figure 1. Cumulative frequency plot showing age at diagnosis of a pineal Figure 2. Scatterplot showing age at diagnosis of intraocular retinoblas- trilateral retinoblastoma in asymptomatic versus symptomatic disease. toma versus age at pineal trilateral retinoblastoma diagnosis. Note the lack of patients diagnosed with pineal trilateral retinoblastoma before retinoblastoma (region in the lower right of the graph), which can be explained by our inclusion criteria: studies reporting on a pineal trilateral retino- Cumulative Frequency of Having Pineal blastoma without intraocular retinoblastoma were excluded. Perhaps (some Trilateral Retinoblastoma Diagnosed of) those patients did not survive long enough for an intraocular retinoblastoma to develop. We stratiﬁed the cumulative frequency of pineal TRb according to the presence or absence of symptoms (Fig 1). The distribution of the ages at which pineal TRb was diagnosed differed pineal TRb was diagnosed also was similar for patients whose signiﬁcantly between the groups (P 0.0026, ManneWhitney intraocular retinoblastoma was diagnosed at the age of 6 months or U test). The 2 cumulative frequency¼ curves were separated by earlier versus those with a later diagnosis, whether analyzing all, approximately 1 year, which we interpret as the lead time from a asymptomatic, or symptomatic patients (P 0.44, P 0.94, and pineal TRb detectable on MRI to the onset of symptoms. The P 0.57, respectively; Fig 2; Appendix¼ F, available¼ at median largest diameter of an asymptomatic versus a symptom- www.aaojournal.org¼ ). atic pineal TRb was 13 mm (interquartile range [IQR], 11e16 The cumulative frequency curve of the interval from diagnosis mm) versus 29 mm (IQR, 22e36 mm; P 0.0004, of an intraocular retinoblastoma to pineal TRb showed that patients ManneWhitney U test). ¼ diagnosed with intraocular retinoblastoma after 6 months of age No correlation between the age at diagnosis of a pineal TRb and demonstrated pineal TRb after a shorter interval than those diag- its diameter was observed (including patients diagnosed before nosed at a younger age, whether considering all, asymptomatic, or 1995 to ensure a larger sample size, because tumor size often was symptomatic patients (Fig 3; P 0.0004, P 0.011, and P unreported; Appendix E, available at www.aaojournal.org) among 0.045, respectively, ManneWhitney¼ U test).¼ Including in the¼ either 31 asymptomatic patients (r e0.11; P 0.56, Spearman) analysis of patients diagnosed with pineal TRb before 1995 or or among 44 symptomatic ones (r¼ e0.15; P¼ 0.33). restricting analysis to that period produced similar results Of 22 patients with an asymptomatic¼ pineal¼ TRb, all but 1 (Appendix G, available at www.aaojournal.org). When comparing patient (95%) were diagnosed before 40 months of age (median, 16 the age at diagnosis of an asymptomatic pineal TRb versus an months of age; IQR, 9e29 months of age; 1 outlier at 56 months of asymptomatic nonpineal TRb, the cumulative frequency curves age; Fig 1). Also, the slope of the cumulative frequency curve for overlapped (Fig 4; P 0.38, ManneWhitney U test). Patients both asymptomatic and symptomatic pineal TRb is nearly with bilateral and unilateral¼ retinoblastoma were diagnosed with consistent, suggesting that the likelihood of being diagnosed with pineal TRb at comparable ages (including patients diagnosed pineal TRb within the period at risk is approximately constant before 1995), whether the intracranial tumor was asymptomatic and unassociated with age. (P 0.52, ManneWhitney U test) or symptomatic (P 0.83; We found no difference in the age at which an asymptomatic Appendix¼ H, available at www.aaojournal.org). ¼ pineal TRb was diagnosed in 11 patients before 1995 (median, 14 months; IQR, 10e36 months) compared with 22 patients in 1995 Prior Treatment and Metachronous Pineal and later (median, 16 months; IQR, 9e29 months; P 0.49, Trilateral Retinoblastoma ManneWhitney U test). The same was true of a symptomatic¼ pineal TRb (median, 34 months [IQR, 24e39 months] vs. 36 months To evaluate the potential effect of previous systemic chemotherapy [IQR, 22e45 months], respectively; P 0.81). The age at which a on the interval from intraocular retinoblastoma to pineal TRb, we ¼ 603 Ophthalmology Volume 127, Number 5, May 2020

AB100% 100%

80% 80%

60% 60%

40% 40% Cumulative frequency Cumulative frequency Cumulative

20% Age at 20% Age at retinoblastoma retinoblastoma diagnosis diagnosis ≤ 6 months ≤ 6 months > 6 months > 6 months

0% 0% 01224364860 01224364860 Interval between retinoblastoma and pineoblastoma Interval between retinoblastoma and pineoblastoma (months) (months)

C 100%

80%

60%

40% Cumulative frequency Cumulative

20% Age at retinoblastoma diagnosis ≤ 6 months > 6 months

0% 01224364860 Interval between retinoblastoma and pineoblastoma (months) Figure 3. Cumulative frequency plots showing the interval between diagnosis of intraocular retinoblastoma and pineal trilateral retinoblastoma in patients diagnosed with intraocular retinoblastoma at 6 months of age or younger and older than 6 months of age (A) for all patients, (B) for asymptomatic patients, and (C) for symptomatic patients. compared patients who were diagnosed with metachronous tumors that a screening program should include scans more frequently than either before or from 1995 onward. Restricting analyses to the once yearly. Assuming that patients with known heritable latter period yielded a small sample size for no chemotherapy retinoblastoma are screened every 6 months until the age of 36 because chemotherapy was prevalent from 1995 onward. Patients months regardless of age at diagnosis of the intraocular tumor, who did not receive prior chemotherapy were diagnosed with pi- this results in a screening MRI scan at the ages of 1, 1.5, 2, 2.5, neal TRb similarly to those who did receive chemotherapy and 3 years. An additional scan at 6 months of age is needed for (Appendix I, available at www.aaojournal.org; P 0.38, familial retinoblastoma screened from birth and for other ManneWhitney U test). Patients who did not receive¼ prior neonatal or early diagnoses.34 These scans also would capture external beam radiotherapy were diagnosed with pineal TRb any rare metachronous nonpineal TRbs. similarly to those who did receive such radiotherapy (Appendix J, Given that 50% of pineal TRbs are diagnosed at the baseline available at www.aaojournal.org; P 0.65, ManneWhitney U MRI scan1 and that 5% of pineal TRbs would be diagnosed after the test). ¼ age of 36 months (assuming that the patient diagnosed with an asymptomatic pineoblastoma at 38 months would have been Potential Implications for Screening diagnosed through MRI performed at 36 months), we estimate a metachronous pineal TRb incidence of 1.6% during the screening A lead time of approximately 1 year (with growth in that time from period. Assuming a sensitivity of 100% for MRI to detect an a median diameter of 13 to 29 mm; and a decrease in 5-year sur- asymptomatic pineal TRb and no symptomatic ones emerging vival from 50% to 21% when diameter exceeds 15 mm)4 suggests between scans, we would need to screen 1/0.016 62.5 patients ¼ 604 de Jong et al Screening for Trilateral Retinoblastoma

100% by the fact that the age at diagnosis of pineal TRb also was unassociated with the laterality of the intraocular retinoblastoma that may reﬂect varying penetrance and expres- sivity of the germline RB1 pathogenic variant during retinal

80% development. We found no association between prior chemotherapy or radiotherapy for intraocular retinoblastoma and the interval to detection of pineal TRb. Consequently, prior treatment probably can be ignored when considering a screening strategy to detect metachronous TRb. 60% Previously,4,38 it was found that nonpineal TRb is diagnosed earlier than pineal TRb. This may be explained in part by a longer lead time bias in the diagnosis of symptomatic pineal TRb; however, pineal tumors are detectable at baseline MRI 40% less frequently than nonpineal TRbs.

Cumulative frequency Cumulative The retinoblastoma community currently agrees that a baseline brain MRI is standard of care to detect a synchronous TRb when intraocular retinoblastoma is diagnosed. 20% Most question the benefit of performing additional imaging Location given the rarity of metachronous TRb. Our results do sug- Pineal gest that, should screening be opted for, it should be inde- Non-pineal pendent of age at which intraocular retinoblastoma is 0% diagnosed. They also suggest that a screening program may 024487296120 be required only until the age of 36 to 40 months and that no Age at diagnosis of trilateral retinoblastoma specific age bracket exists that would require a variable (months) screening approach (e.g., more or less frequent screening). Figure 4. Cumulative frequency plot showing age at diagnosis of trilateral With an estimated incidence of metachronous pineal TRb of retinoblastoma for patients with pineal versus nonpineal trilateral less than 2% in patients with heritable retinoblastoma, any retinoblastoma. screening program would require hundreds of MRI scans to detect 1 patient with an asymptomatic pineal TRb, and thus fi with MRI to diagnose 1 asymptomatic metachronous pineal TRb. should undergo a thorough cost-bene t scrutiny. Assuming an even distribution of diagnoses during the screening interval from 6 to 36 months (i.e., 0.2 positive scan every Study Limitations 6 months), we would require 62.5 scans in the first round and 62.3, 62.1, 61.9, and 61.7 subsequent rounds, amounting to 310.5 As noted in the previously published meta-analysis,4 our MRI scans in total. With a survival rate of approximately 50% for study is limited similarly by the heterogeneity of included asymptomatic and 10% for symptomatic patients,4 the screening patients. The problem of potential publication bias is program would be able to save 1 life for every 310.5 / 0.5 5/ illustrated by the checklist that showed that up to 71% of 4 776.25 MRI scans. These numbers will increase with a lowerÂ ¼ studies presented case reports or small case series, sensitivity of MRI and any symptomatic interval pineal TRb. suggesting that the cases may not represent the entire Also, the possibility of overdiagnosis (false-positive result) would risk unnecessary treatment with its associated morbidity and experience of the center. Furthermore, in 18% of studies, mortality. High-dose chemotherapy with stem cell rescue caries a the possibility cannot be excluded that at least 1 of the risk of toxic adverse effects, including death reported in 1 of 41 patients in a particular series did not represent a false- cases.35e37 positive diagnosis, either because of deficient follow-up or because normal pineal glands sometimes may be difficult to 39,40 Overall Level of Evidence differentiate from a small pineal TRb. However, the age at diagnosis of pineal TRb did not differ significantly in the Appendix K (available at www.aaojournal.org) outlines the group of patients with versus without confirmation. GRADE (Grading of Recommendations Assessment, Ideally, our research question and protocol would have Development and Evaluation) level of evidence. The overall been solved and published earlier. However, the research level of evidence is of low quality, that is, this research provides some indication of the likely effect. However, the likelihood that question emerged from a recent unpredicted diagnosis of a it will be substantially different (a large enough difference that it metachronous pineal TRb by the coauthors from Toronto, might have an effect on a decision) is high. Canada (B.G., S.E.S., F.S., and H.D.), which led to contact with the authors of the previous meta-analysis on survival after TRb.4 As a result, the prior meta-analysis protocol was Discussion adapted to provide the required answers. In conclusion, age at diagnosis of heritable intraocular We found that the age at which intraocular retinoblastoma retinoblastoma and pineal TRb likely are independent. Age and pineal TRb are diagnosed are unassociated with each at diagnosis of an asymptomatic nonpineal TRb and an other. This suggests independent development of intraocular asymptomatic pineal TRb are similar and are unassociated retinoblastoma and pineal TRb, a conclusion strengthened with the age at diagnosis and laterality of the intraocular

605 Ophthalmology Volume 127, Number 5, May 2020 retinoblastoma. The lead time from a detectable pine- 16. Gupta AK, Jones M, Prelog K, et al. Pineal cysts: a benign oblastoma on MRI to development of symptoms is association with familial retinoblastoma. Pediatr Hematol approximately 1 year. Prior systemic chemotherapy or Oncol. 2016;33(6):408e414. radiotherapy for intraocular retinoblastoma is not associated 17. Leila S, Ibtissam H, Hafsa E, Abdeljalil M. Extra-ocular reti- with the age at diagnosis of pineal TRb. Ninety-ﬁve percent noblastoma: about 12 cases followed at the Mohamed VI Uni- versity Hospital of Marrakech. Pan Afr Med J. 2016;25:131. of patients with an asymptomatic pineal TRb are diagnosed 18. Selistre SGA, Maestri MK, Santos-Silva P, et al. Retinoblas- before the age of 40 months, which can be considered the toma in a pediatric oncology reference center in Southern period at risk of a pineal TRb developing. During this Brazil. 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Footnotes and Financial Disclosures

Originally received: March 26, 2019. Financial Disclosure(s): Final revision: October 19, 2019. The author(s) have no proprietary or commercial interest in any materials Accepted: October 28, 2019. discussed in this article. Available online: November 9, 2019. Manuscript no. 2019-658. HUMAN SUBJECTS: Human subjects were included in this study. The 1 Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije human ethics committees at VU Medisch Centrum approved the study with Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The a waiver of informed consent. All research adhered to the tenets of the Netherlands. Declaration of Helsinki. 2 Department of Pediatric Oncology, Amsterdam UMC, Vrije Universiteit No animal subjects were included in this study. Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands. Author Contributions: 3 Department of Ophthalmology, Amsterdam UMC, Vrije Universiteit Conception and design: de Jong, Moll, de Graaf, Dimaras, Kivelä Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands. Analysis and interpretation: de Jong, Kors, Moll, de Graaf, Castelijns, 4 Department of Ophthalmology and Vision Science, The Hospital for Sick Jansen, Gallie, Soliman, Shaikh, Dimaras, Kivelä Children, Toronto, Canada. Data collection: de Jong, Kors, Moll, Soliman, Shaikh, Kivelä 5 Department of Ophthalmology and Vision Science, University of Toronto, Obtained funding: N/A Toronto, Canada. 6 Overall responsibility: de Jong, Kors, Moll, de Graaf, Castelijns, Jansen, Faculty of Medicine, Department of Ophthalmology, University of Gallie, Soliman, Shaikh, Dimaras, Kivelä Alexandria, Alexandria, Egypt. Abbreviations and Acronyms: 7 Department of Pediatrics, University of Toronto, Toronto, Ontario, GRADE Grading of Recommendations Assessment, Development and Canada. Evaluation;¼ IQR interquartile range; MRI magnetic resonance im- 8 ¼ ¼ Child Health Evaluative Sciences Program, SickKids Research Institute, aging; TRb trilateral retinoblastoma. Toronto, Canada. ¼ Correspondence: 9 Division of Clinical Public Health, Dalla Lana School of Public Health, Marcus C. de Jong, MD, PhD, Department of Radiology and Nuclear University of Toronto, Toronto, Canada. Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, P.O. Box 10 Department of Ophthalmology, University of Helsinki and Helsinki 7057, 1007 MB Amsterdam, The Netherlands. E-mail: mc.dejong@ University Hospital, Helsinki, Finland. vumc.nl.

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