Global Retinoblastoma Study Group IMPORTANCE Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale.OBJECTIVES To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. DESIGN, SETTING, AND PARTICIPANTSA total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. MAIN OUTCOMES AND MEASURESAge at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. RESULTSThe cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low-and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI,, and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI,). CONCLUSIONS AND RELEVANCEThis study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

Previous studies examining sun exposure and ocular melanoma have produced inconsistent results. We investigated this association in a population-based case-control study in Australia. Cases (n ‫؍‬ 290) aged 18 -79 years were diagnosed between January 1996 and July 1998. Controls (n ‫؍‬ 893) were randomly selected from the electoral rolls and frequencymatched to cases by age, sex and state. A self-administered questionnaire and a telephone interview measured sun exposure on weekdays and weekends at 10, 20, 30 and 40 years of age and over the whole of life for specific jobs and recreations. Multivariate logistic regression models of ocular melanoma and sun exposure contained age, sex, region of birth, eye color and measures of ocular and cutaneous sun sensitivity as covariates. Choroid and ciliary body melanoma (n ‫؍‬ 246) was positively associated with time outdoors on weekdays and, less persuasively, total time outdoors but not ambient solar irradiance. Odds ratios increased with increasing exposure to OR 1.8 (95% confidence interval 1.1-2.8) for the highest quarter of sun exposure on weekdays up to 40 years of age for men and women together. The strongest positive associations were for total exposure up to 40 years of age, lifetime occupational exposure and total exposure at about 20 years of age in men; all had odds ratios between 2 and 3 in the highest exposure categories. There was inconclusive evidence for an association between sun exposure and iris (n ‫؍‬ 25) or conjunctival (n ‫؍‬ 19) melanomas. Sun exposure is an independent risk factor for choroidal and ciliary body melanoma in Australia. © 2002 Wiley-Liss, Inc. Key words: ocular melanoma; aetiology; sun exposure; UV radiation; AustraliaThe estimated risks of ocular melanoma associated with personal sun exposure, ambient solar irradiance and use of protective wear have been inconsistent both within and between case-control studies. [1][2][3][4][5][6][7][8][9] However, positive associations with factors less prone to measurement error, such as indicators of sun sensitivity 10 and exposure to artificial sources of UV radiation (e.g., welding arcs and sunlamps), 4,9 suggest a positive association with solar radiation.Possible explanations for past inconclusive results include nonpopulation-based ascertainment of cases and controls, use of qualitative or crude quantitative sun-exposure measures and inadequate control of potential confounding factors, particularly sun sensitivity. Moreover, previous studies collected little or no sun-exposure data for the early years of life. If sun exposure is a risk factor for melanoma of the choroid and ciliary body, the commonest subsites of ocular melanoma, the aetiologically relevant exposure period is probably from birth to the early 20s, when there is some transmission of UV radiation by the crystalline lens to these posterior ocular sites. 11,12 Finally, the unique exposure characteristics of the eye necessitate accounting for personal protective behaviors and environmental factors in estimating ocular sun exposure...

Routinely collected incidence data have often lacked specific identification of ocular melanoma in the past and with increasing diagnosis and management of this disease by noninvasive techniques may now underestimate the true incidence. We attempted to accurately measure the incidence of ocular melanoma in Australia from 1990 to 1998 using 2 population-based sources, cancer registries and ophthalmologists. We examined the distribution across the continent, by latitude and in subpopulations, and evaluated the extent of nonnotification to cancer registries. One-half (51%) of the incident cases from 1996 to 1998 were diagnosed clinically and had no tissue diagnosis. An estimated 20% of melanomas, mainly those lacking a tissue diagnosis, were not notified to Australian cancer registries, but only 1.3% were not notified by ophthalmologists. Expert reviewers agreed that a high proportion (95%) of clinically diagnosed lesions were probable or possible melanomas. Incidence was significantly higher in men than in women, especially at older ages, relatively uniform across the Australian states with only weak evidence of a latitude gradient, and higher in rural than in urban areas. The incidence of ocular melanoma in people born in Southern Europe was half and in those born in Asia only 20% of the rate in people born in Australia and New Zealand. We concluded that it was possible to identify a high proportion of cases by surveying relevant sources additional to cancer registries and to be reasonably confident of the accuracy of the clinical diagnoses. The higher incidence in older men, who probably have higher sun exposure, than in older women and in residents of rural areas, where outdoor work is more prevalent, than in urban areas; the low incidence in dark-eyed populations, who may have a lower sensitivity to or less transmission of solar radiation to the choroid; and the preferential location of ocular melanomas in ocular sites known to receive the highest exposure to solar radiation all support a role for solar radiation in the aetiology of ocular melanoma. The absence of a strong latitude gradient in incidence does not argue against such a role because exposure of the eye to solar UV is probably determined most by the horizon sky, where ambient solar UV is less affected by latitude.

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