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      Global Retinoblastoma Presentation and Analysis by National Income Level

      Global Retinoblastoma Study Group , MD , 1 , 2 , , MD 3 , , MD 4 , , MD 5 , , MD 6 , , FMCOph, FWACS 7 , , FWACS 8 , , MD 9 , , MD 10 , , MSc, FMCOph 11 , , MRCPCH 12 , , MD 13 , , MD 14 , , MD 15 , , MD 16 , , MD 17 , , MD 18 , , MD 19 , , MD 20 , , MD 21 , , MD 22 , , MD 23 , , MD 24 , , MD 25 , , MD, MSc 26 , , MD 27 , , MD 28 , , MD 18 , , MD 29 , , MD 20 , , MD, PhD 30 , , FIBMS 31 , , MD 32 , , MD 33 , , MD 5 , , MD 34 , , MD 35 , , MD 36 , , FRCS, FRCOphth 1 , , MD 37 , , MD 38 , , OCO 39 , , MD 40 , , MRCSEd 41 , 42 , , MD 43 , , MD, PhD 44 , , PhD 16 , , MD 45 , , MD, PhD 44 , , MD, MSc 1 , , MD 46 , , MD 47 , , MD 48 , , MD, PhD 49 , , MD, PhD 50 , , MD 51 , , MS 52 , , MD 53 , , FCOph 54 , , MD 55 , , MD 56 , 55 , , MD 57 , , MD, PhD 58 , , MD 55 , , MD 59 , , MD, PhD 60 , , MD 61 , , MD 62 , , MD, PhD 63 , , MD 38 , , MD 64 , , MD 65 , , FRANZCO 66 , , MD, MSc 67 , , FRCPI 68 , , MD, PhD 69 , , MD 70 , , MD 71 , , MD, PhD 72 , , MD, PhD 72 , 73 , 74 , , MD 75 , , MD 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143 , , MD 144 , , FCPS 145 , , MSc 146 , , MD 147 , , MD 148 , , MD 147 , , MD 37 , , MD, FWACS 4 , , FRCS, FCPS 149 , , MD 150 , , MD 151 , , MD 96 , , MD 152 , , MD 153 , , MD 154 , , MD 155 , , MD 156 , , MD 150 , , MD 157 , , MD 36 , , MD 158 , , DNB 159 , , FRCOphth 114 , , MD, PhD 160 , , MD 89 , , MD, PhD 161 , , MD 162 , , MD 163 , , MD, PhD, FRANZCO 102 , , MD, PhD 164 , , MD 59 , , MD 165 , , MD 166 , , MD 167 , , MD 168 , , PhD 169 , , MD 170 , , MD 171 , , BMedSc 129 , , MD 172 , , MD 173 , , MD 174 , , MD 175 , , FRCS 176 , , MD 126 , , MD 169 , , MD 51 , , MD, PhD 177 , , MD 178 , , MD 179 , , MD, PhD 180 , , MD 181 , , MD, PhD 182 , , MMedPaed, PhD 183 , , MD 184 , , MD 35 , , BA 80 , , MD 185 , , FCOphth 186 , , FRANZCO 187 , , MD 57 , , MD, PhD 188 , , MD 189 , , MD 190 , , MD 191 , , MD 192 , , MD 193 , , MD 194 , , FRCS(Ed), MMedOphth 195 , , MD 196 , , MD 197 , , MD 98 , , MD 198 , , MD 199 , , MD 200 , , MD 163 , , MD 201 , , MPPA 135 , , MD 88 , , MD 202 , , MD 203 , , MMedOphth 122 , , MD, PhD 17 , , MBA 204 , , MD 204 , , MD, MMedOphth 39 , , MD 175 , , MD 137 , , BAPH 205 , , MD 54 , , MD, MMedPaed 206 , , MD 108 , 207 , , MD, PhD 208 , , MD 209 , , MD 210 , , MD 211 , , MD 19 , , MD 189 , , MD, PhD 212 , , DNB 213 , , MD 214 , , FRCPath 215 , , MD, FRCS 216 , , MD, PhD 217 , , MD 218 , , MD 64 , , MD, PhD 219 , , MD, MHS 154 , , MMedOphth 214 , , MMedOphth 122 , , DNBPediatric 141 , , MMedOphth, FCOphth 220 , , MD 221 , , MD 84 , , MD, MBA 128 , , FWACS, FMCOphth, FICO 222 , , MD 12 , , MD 191 , , MD 223 , , MMedPaed, PhD 54 , , MD 224 , 225 , , MD, PhD 226 , , MD, PhD 227 , , MD 228 , , MD, PhD 229 , , MD 230 , , MD 218 , , MD, PhD 158 , , FMCOph 231 , , MD 113 , , FRCS 232 , , MD, MMedOphth, FCOphth 233 , , MD 234 , , MB, BS, FWASC, FAEH 11 , , MD 82 , , MD 235 , , MD, FWACS 236 , , MD 237 , , MD 148 , , MD, PhD 13 , , FRCOphth 160 , , FWACP 236 , , MD 238 , , FECF, FICO 239 , , FRCSED 213 , , MD 240 , , MD, PhD 212 , , MS, FRCOphth 160 , , MD 151 , , MD, FRCSC 241 , , MD, PhD 45 , , MD 119 , , MD 120 , , MD, PhD 242 , , MD 243 , , MD 244 , , MD 86 , , MD, PhD 245 , , MD 246 , , MD 247 , 248 , , MD, PhD 249 , , MD 250 , , MD 2 , , MD 176 , , BS 251 , , MD 252 , , FCPS 12 , , MD 253 , , MD 106 , , MD 9 , , MD 146 , , MD 194 , , MD 213 , , MD 77 , , MD, MPH 254 , , MD 255 , , MS 256 , , FRCOphth 14 , , MD 257 , , FRCPCH 258 , , MD 259 , , FMCOph 260 , , MD 261 , , MD 262 , , MD 40 , , MD 134 , , DCO 232 , , MD 263 , , MD, PhD 229 , , MD 18 , , FRCS(Ed) 264 , , MD 265 , , MD 194 , , MD 266 , , MD 267 , , MD 268 , , MD 269 , , MRCPI, MSc 80 , , MD 42 , , MSc 259 , , MD 270 , , MD, PhD 30 , , DNB MNAMS 271 , , MD, PhD 131 , , MS 272 , , MD 273 , , MD 127 , , MS 274 , , MD 275 , , MD 149 , , MD, PhD 276 , , MD 70 , , MD 94 , , MS 176 , , MS 277 , , MD 91 , , MD, PhD 278 , , MD, PhD 279 , , MD, PhD 199 , , MD, PhD 56 , , MD 280 , , MD 281 , , PhD 108 , 282 , , MD 283 , , MD 221 , , MD, PhD 249 , , MBChB, FCPaed 284 , , MD 285 , , MD 286 , , FCPS 256 , , MD 287 , , MD 279 , , MD 144 , , MD, PhD 251 , , MD 288 , , MD, PhD 289 , , MD, PhD 290 , , MD 291 , , MD, PhD 240 , , MBBS 195 , , MD, PhD 28 , , MD 292 , , MD 209 , , MD, PhD 293 , , MD 294 , , MD 103 , 295 , , MD 146 , , MSc 296 , , MBChB 297 , , MD 243 , , MD 298 , , MD 288 , , MD 299 , , MD 300 , , MD, FMCPath 4 , , MD 301 , , BA 155 , , MD, PhD 302 , , MD 247 , 248 , , MD 303 , , MD 304 , , MD 217 , , MD 184 , , MD 292 , , FRCS(Ed) 87 , , MD, PhD 79 , , MD 142 , , MD, PhD 278 , , MD 304 , , MD 65 , , MD 2 , , MD 274 , , MD 99 , , MD 305 , , DM, FRCP, FRCS, FRCOphth 205 , , MBBS 306 , , MD, FMCOph 307 , , MD 308 , , MD 281 , , MD 309 , , MD 238 , , MD 310 , , MD 310 , , MD 17 , , MD, PhD 311 , , MD, PhD 312 , , MSc 313 , , FRCSEd 186 , , MD 314 , , MD 315 , , MD, FCPS, FRCSEd 316 , , MD 317 , , MD, PhD 317 , , MD 314 , , MD 216 , , MD 107 , , MD 99 , , MD 318 , , MD 319 , , MD, PhD 308 , , MD 319 , , MD 320 , , MD 226 , , MBBS, MCPS 145 , , MD, PhD 265 , , MBA 1 , , FRCOphth 1 , 321

      JAMA Oncology

      American Medical Association

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          This cross-sectional analysis reports the retinoblastoma stage at diagnosis across the world during a single year, investigates associations between clinical variables and national income level, and investigates risk factors for advanced disease at diagnosis.

          Key Points

          Question

          Is the income level of a country of residence associated with the clinical stage of presentation of patients with retinoblastoma?

          Findings

          In this cross-sectional analysis that included 4351 patients with newly diagnosed retinoblastoma, approximately half of all new retinoblastoma cases worldwide in 2017, 49.1% of patients from low-income countries had extraocular tumor at time of diagnosis compared with 1.5% of patients from high-income countries.

          Meaning

          The clinical stage of presentation of retinoblastoma, which has a major influence on survival, significantly differs among patients from low-income and high-income countries, which may warrant intervention on national and international levels.

          Abstract

          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 Participants

          A 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 Measures

          Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis.

          Results

          The 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, 12.94-24.80], and for lower-middle–income countries vs upper-middle–income countries and HICs, 5.74 [95% CI, 4.30-7.68]).

          Conclusions and Relevance

          This 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.

          Related collections

          Most cited references 25

          • Record: found
          • Abstract: not found
          • Article: not found

          Tests for Linear Trends in Proportions and Frequencies

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            Retinoblastoma

            Retinoblastoma is a rare cancer of the infant retina that is diagnosed in approximately 8,000 children each year worldwide. It forms when both retinoblastoma gene (RB1) alleles are mutated in a susceptible retinal cell, probably a cone photoreceptor precursor. Loss of the tumour-suppressive functions of the retinoblastoma protein (pRB) leads to uncontrolled cell division and recurrent genomic changes during tumour progression. Although pRB is expressed in almost all tissues, cone precursors have biochemical and molecular features that may sensitize them to RB1 loss and enable tumorigenesis. Patient survival is >95% in high-income countries but <30% globally. However, outcomes are improving owing to increased disease awareness for earlier diagnosis, application of new guidelines and sharing of expertise. Intra-arterial and intravitreal chemotherapy have emerged as promising methods to salvage eyes that with conventional treatment might have been lost. Ongoing international collaborations will replace the multiple different classifications of eye involvement with standardized definitions to consistently assess the eligibility, efficacy and safety of treatment options. Life-long follow-up is warranted, as survivors of heritable retinoblastoma are at risk for developing second cancers. Defining the molecular consequences of RB1 loss in diverse tissues may open new avenues for treatment and prevention of retinoblastoma, as well as second cancers, in patients with germline RB1 mutations.
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              A proposal for an international retinoblastoma staging system.

              Although intra-retinal tumor has long been staged presurgically according to the Reese-Ellsworth (R-E) system, retinoblastoma differs from other pediatric neoplasms in never having had a widely accepted classification system that encompasses the entire spectrum of the disease. Comparisons among studies that consider disease extension, risk factors for extra-ocular relapse, and response to therapy require a universally accepted staging system for extra-ocular disease. A committee of retinoblastoma experts from large centers worldwide has developed a consensus classification that can encompass all retinoblastoma cases and is presented herein. Patients are classified according to extent of disease and the presence of overt extra-ocular extension. In addition, a proposal for substaging considering histopathological features of enucleated specimens is presented to further discriminate between Stage I and II patients. The following is a summary of the classification system developed-Stage 0: Patients treated conservatively (subject to presurgical ophthalmologic classifications); Stage I: Eye enucleated, completely resected histologically; Stage II: Eye enucleated, microscopic residual tumor; Stage III: Regional extension [(a) overt orbital disease, (b) preauricular or cervical lymph node extension]; Stage IV: Metastatic disease [(a) hematogenous metastasis: (1) single lesion, (2) multiple lesions; (b) CNS extension: (1) prechiasmatic lesion, (2) CNS mass, (3) leptomeningeal disease]. A proposal is also presented for substaging of enucleated Stages I and II eyes. The proposed staging system is the product of an international effort to adopt a uniform staging system for patients with retinoblastoma to cover the whole spectrum of the disease. (c) 2005 Wiley-Liss, Inc.
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                Author and article information

                Journal
                JAMA Oncol
                JAMA Oncol
                JAMA Oncol
                JAMA Oncology
                American Medical Association
                2374-2437
                2374-2445
                May 2020
                27 February 2020
                27 February 2020
                : 6
                : 5
                : 1-12
                Affiliations
                [1 ]International Centre for Eye Health, London School of Hygiene & Tropical Medicine, London, United Kingdom
                [2 ]The Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Tel Aviv University, Tel Aviv, Israel
                [3 ]Ophthalmology Department of Rabat, Mohammed V University, Rabat, Morocco
                [4 ]Aminu Kano Teaching Hospital, Bayero University, Kano, Nigeria
                [5 ]Basra Children’s Specialty Hospital, Basra, Iraq
                [6 ]National Hospital of Niamey, Niamey, Niger
                [7 ]University of Ilorin Teaching Hospital, University of Ilorin, Ilorin, Nigeria
                [8 ]Department of Ophthalmology, University of Port Harcourt Teaching Hospital, Port Harcourt, Nigeria
                [9 ]University of California, San Francisco
                [10 ]Department of Pediatrics, Banaras Hindu University, Varanasi, India
                [11 ]Department of Ophthalmology, College of Medicine, University of Nigeria, Enugu, Nigeria
                [12 ]The Children’s Hospital and the Institute of Child Health, Lahore, Pakistan
                [13 ]RS Dr Wahidin Sudirohusodo, Makassar, Indonesia
                [14 ]The Royal London Hospital, Barts Health NHS Trust, and Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom
                [15 ]Hawler Medical University, Erbil, Iraq
                [16 ]Zarifa Aliyeva National Center of Ophthalmology, Baku, Azerbaijan
                [17 ]Department of Pediatric Ophthalmology, Hospital Vall d’Hebron, Barcelona, Spain
                [18 ]Pediatric Oncology Unit, Children Welfare Teaching Hospital, College of Medicine, University of Baghdad, Baghdad, Iraq
                [19 ]Philippine General Hospital, University of the Philippines, Manila, Philippines
                [20 ]College of Medicine, King Saud University, Riyadh, Saudi Arabia
                [21 ]Unidad Nacional de Oncología Pediátrica, Guatemala City, Guatemala
                [22 ]Instituto Cubano de Oftalmología Ramón Pando Ferrer, Marianao, Havana, Cuba
                [23 ]University of Parakou, Parakou, Benin
                [24 ]St Damien Pediatric Hospital, Port-au-Prince, Haiti
                [25 ]Department of Ophthalmology, American University of Beirut Medical Center, Beirut, Lebanon
                [26 ]Pediatric Oncology Department, National Oncology Center, Sana’a, Yemen
                [27 ]Pediatric Oncology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
                [28 ]University Hospital Center Mother Theresa, Tirana, Albania
                [29 ]Imam Hussein Cancer Center, Karbala, Iraq
                [30 ]St Erik Eye Hospital, Stockholn, Sweden
                [31 ]Ibn Al Haitham Teaching Eye Hospital, Baghdad, Iraq
                [32 ]Beira Central Hospital, Beira, Mozambique
                [33 ]Tripoli Eye Hospital, University of Tripoli, Tripoli, Libya
                [34 ]Oncology Unit, Child’s Central Teaching Hospital, Baghdad, Iraq
                [35 ]National Eye Center, Cicendo Eye Hospital, Bandung, Indonesia
                [36 ]Bambino Gesù IRCCS Children’s Hospital, Rome, Italy
                [37 ]Department of Ophthalmology, School of Medicine, Gazi University, Ankara, Turkey
                [38 ]Siriraj Hospital, Mahidol University, Bangkok, Thailand
                [39 ]Lighthouse For Christ Eye Centre, Mombasa, Kenya
                [40 ]Department of Ophthalmology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
                [41 ]Yangon Eye Hospital, University of Medicine 1, Yangon, Myanmar
                [42 ]Retina Consultants of Houston, Houston, Texas
                [43 ]Scientific Center of Pediatrics and Pediatric Surgery, Almaty, Kazakhstan
                [44 ]Pediatric Oncology Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain
                [45 ]Institute of Pediatrics, Jagiellonian University Medical College, Children’s University Hospital of Krakow, Krakow, Poland
                [46 ]Pediatric Hematology-Oncology Unit, Lausanne University Hospital, Lausanne, Switzerland
                [47 ]Hospital Nacional de Niños Dr Carlos Sáenz Herrera, San Jose, Costa Rica
                [48 ]Department of Pediatric Oncology, University Hassan II Fès, Fez, Morocco
                [49 ]Center Hospitalier et Universitaire Ibn Rochd, Casablanca, Morocco
                [50 ]Ophthalmologic Department of the Teaching Hospital of Treichville, Abidjan, Côte d’Ivoire
                [51 ]Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles
                [52 ]The Calcutta Medical Research Institute, Kolkata, India
                [53 ]Department of Pediatric Hematology and Oncology, Narayana Health City, Bangalore, India
                [54 ]University of the Witwatersrand, Johannesburg, South Africa
                [55 ]Department of Ophthalmology, Essen University Hospital, University Duisburg-Essen, Essen, Germany
                [56 ]The Filatov Institute of Eye Diseases and Tissue Therapy, Odessa, Ukraine
                [57 ]Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City
                [58 ]Hospital das Clínicas da FMUSP, São Paulo, Brazil
                [59 ]Centre Hospitalier Universitaire Yalgado Ouédraogo de Ouagadougou, Ouagadougou, Burkina Faso
                [60 ]Institut Hédi Raïs d’Ophtalmologie, Faculté de Médecine, Université Tunis El Manar, Tunis, Tunisia
                [61 ]Etablissement Hospitalière Spécialise Emir Abdelkader CEA Service d’Oncologie Pédiatrique, Oran, Algeria
                [62 ]Solid Tumor Division, Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee
                [63 ]Cliniques Universitaires Saint-Luc, Brussel, Belgium
                [64 ]Hospital Infantil Manuel de Jesús Rivera, Managua, Nicaragua
                [65 ]Hospital del Niño Dr. Francisco De Icaza Bustamante, Guayaquil, Ecuador
                [66 ]Department of Ophthalmology, Queensland Children's Hospital, Brisbane, Queensland, Australia
                [67 ]Salud Ocular, Ministerio de Salud Publica, Asuncion, Paraguay
                [68 ]Our Lady’s Children’s Hospital, Dublin, Ireland
                [69 ]Institut Curie, Université de Paris Medicine Paris V Descartes, Paris, France
                [70 ]Centro Hospital Universitário de Coimbra, University of Coimbra, Coimbra, Portugal
                [71 ]Hospital Pereira Rossell, Montevideo, Uruguay
                [72 ]Hospital Sant Joan de Déu, Barcelona, Spain
                [73 ]Hospital Garrahan, Buenos Aires, Argentina
                [74 ]NationalScientific and Technical Research Council, CONICET, Buenos Aires, Argentina
                [75 ]Paediatric Ophthalmology Department, Mayo Hospital and College of Allied Visual Sciences, King Edward Medical University, Lahore, Pakistan
                [76 ]Department of Ophthalmic Plastic Surgery, Orbit and Ocular Oncology, PBMA’s H. V. Desai Eye Hospital, Pune, Maharashtra, India
                [77 ]University of Louisville, Louisville, Kentucky
                [78 ]Ocular Oncology Service, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
                [79 ]Eye Clinic, Department of Ophthalmology, University Hospital Alexandrovska, Medical University, Sofia, Sofia, Bulgaria
                [80 ]Muhimbili National Hospital, Dar es Salaam, Tanzania
                [81 ]National Center for Maternal and Children Health of Mongolia, Ulaanbaatar, Mongolia
                [82 ]Department of Ophthalmology, The Children’s Memorial Health Institute, Warsaw, Poland
                [83 ]Starship Children’s Health, Auckland, New Zealand
                [84 ]Institute of Oncology, Prof. Dr Al. Trestioreanu, Bucharest, Romania
                [85 ]Wilmer Eye Institute, Johns Hopkins Medicine, Baltimore, Maryland, and University of Cincinnati College of Medicine, Cincinnati, Ohio
                [86 ]Indiana University Medical Center, Indianapolis
                [87 ]Bustamante Hospital for Children, Kingston, Jamaica
                [88 ]Semmelweis University, Budapest, Hungary
                [89 ]Department of Ophthalmology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
                [90 ]Quelimane Central Hospital, Quelimane, Mozambique
                [91 ]Department of Ophthalmology, Songklanagarind Hospital, Prince of Songkla University, Songkla, Thailand
                [92 ]Department of Pediatric Hematology-Oncology, Tata Medical Center, Kolkata, India
                [93 ]Ocular Oncology Services, Dr Shroff’s Charity Eye Hospital, New Delhi, India
                [94 ]Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
                [95 ]Red Cross War Memorial Children’s Hospital and the University of Cape Town, Cape Town, South Africa
                [96 ]National Children’s Hospital, Panama City, Panama
                [97 ]Department of Ophthalmology, Kellogg Eye Center, University of Michigan, Ann Arbor
                [98 ]Institut Curie, Paris, France
                [99 ]Instituto Nacional de Enfermedades Neoplasicas, Lima, Perú
                [100 ]The Hospital for Sick Children, Toronto, Ontario, Canada
                [101 ]Department of Paediatrics, University of Otago, Christchurch, Children’s Haematology and Oncology Center, Christchurch Hospital, Christchurch, New Zealand
                [102 ]The Children’s Hospital at Westmead, Sydney, New South Wales, Australia
                [103 ]Pediatric Oncology Institute, Federal University of São Paulo, São Paulo, Brazil
                [104 ]Department of Ophthalmology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
                [105 ]University of KwaZulu-Natal, Durban, South Africa
                [106 ]Ophthalmology Department, Dr M. Djamil General Hospital, Faculty of Medicine, Andalas University, West Sumatra, Indonesia
                [107 ]Department of Ophthalmology, Faculty of Medicine, Udayana University, Sanglah Eye Hospital, Bali, Indonesia
                [108 ]Department of Ophthalmology, Royal Children’s Hospital, Parkville, Victoria, Australia
                [109 ]Department of Paediatrics, Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia
                [110 ]Children’s Cancer Hospital Egypt 57357, Cairo, Egypt
                [111 ]Department of Oncology, National Cancer Institute, University of Gezira, Wadi Madani, Sudan
                [112 ]Ophthalmology Unit, Department of Surgery, School of Medicine and Dentistry, University of Ghana, Accra, Ghana
                [113 ]Magrabi ICO Cameroon Eye Institute, Yaounde, Cameroon
                [114 ]Aga Khan University, Karachi, Pakistan
                [115 ]Pediatric Growth and Development Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Rasool Akram Hospital, Tehran, Iran
                [116 ]Department of Ophthalmology, University College Hospital, University of Ibadan, Ibadan, Nigeria
                [117 ]Mi Clinic, Ciudad del Este, Paraguay
                [118 ]Hospital Universitario Virgen Macarena, Sevilla, Spain
                [119 ]Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
                [120 ]Hospital Escuela, Tegucigalpa, Honduras
                [121 ]Pediatric Oncology Department, Benjamin Bloom National Children’s Hospital, San Salvador, El Salvador
                [122 ]Lions Sight First Eye Hospital, Queen Elizabeth Central Hospital, Blantyre, Malawi
                [123 ]ClínicaAnglo American, Lima, Perú
                [124 ]Servicio Andaluz de Salud, Sevilla, Spain
                [125 ]Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa
                [126 ]Retina and Vitreous Service, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
                [127 ]Department of Ophthalmology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia
                [128 ]Murray Ocular Oncology and Retina, Miami, Florida
                [129 ]Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
                [130 ]Department of Ophthalmology, Sourasky Medical Center Tel Aviv, School of Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
                [131 ]Department of Ophthalmology, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts
                [132 ]Hospital Civil de Guadalajara, Guadalajara, Mexico
                [133 ]Pediatric Oncology Unit, Instituto Regional de Enfermedades Neoplásicas del Sur, Arequipa, Perú
                [134 ]Unidad de Oncologia Ocular Hospital Oncologico Luis Razzetti, Caracas, Venezuela
                [135 ]IAM NOOR Eye Care Programme, Afghanistan
                [136 ]Department of Clinical Genetics and Center for Rare Disorders, Aarhus University Hospital, Aarhus, Denmark
                [137 ]National Cancer Institute, Rio de Janeiro, Brazil
                [138 ]Département de Pédiatrie, CHU Sylvanus Olympio, Université de Lomé, Lomé, Togo
                [139 ]National Cancer Institute, Maharagama, Sri Lanka
                [140 ]Department of Ophthalmology, Ankara University School of Medicine, Ankara, Turkey
                [141 ]Bai Jerbai Wadia Hospital for Children, Mumbai, India
                [142 ]King George’s Medical University, Lucknow, India
                [143 ]Retinoblastoma Referral Center, University of Siena, Siena, Italy
                [144 ]Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montréal, Quebec, Canada
                [145 ]The Indus Hospital, Karachi, Pakistan
                [146 ]Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
                [147 ]John A. Moran Eye Center, University of Utah, Salt Lake City
                [148 ]Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida
                [149 ]Department of Pediatric Ophthalmology and Strabismus, Al Shifa Trust Eye Hospital, Rawalpindi, Pakistan
                [150 ]University Children’s Hospital, Bratislava, Slovakia
                [151 ]Hospital Nacional Guillermo Almenara Irigoyen, Lima, Perú
                [152 ]Pediatric Hematology and Oncology Center, Mohammed V University, Rabat, Morocco
                [153 ]Department of Pediatrics and Child Health, Jimma University Medical Center, Jimma, Ethiopia
                [154 ]Byers Eye Institute, Stanford University, Stanford, California
                [155 ]Emory Eye Center, Atlanta, Georgia
                [156 ]Department of Ophthalmology, Oslo University Hospital, Oslo, Norway
                [157 ]Oncology Unit, Child’s Central Teaching Hospital, Baghdad, Iraq
                [158 ]Institute for Oncology and Radiology of Serbia, Belgrade, Serbia
                [159 ]Pacific International Hospital, Port Moresby, Papua New Guinea
                [160 ]Eye Department, Birmingham Children’s Hospital, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom
                [161 ]Fight Against Angiogenesis-Related Blindness Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
                [162 ]Clínica Oftalmológica Pasteur, Santiago, Chile
                [163 ]Storm Eye Institute, Medical University of South Carolina, Charleston
                [164 ]Bukavu Eye Clinic, Bukavu Official University, Bukavu, Democratic Republic of the Congo
                [165 ]Operation Eyesight Universal Institute for Eye Cancer, L V Prasad Eye Institute, Hyderabad, India
                [166 ]Department of Ophthalmology, Makerere University College of Health Sciences Kamplala, Uganda
                [167 ]Division of Pediatric Oncology, School of Medicine, Ege University, Izmir, Turkey
                [168 ]Chang Gung Memorial Hospital, Taipei, Taiwan
                [169 ]Ophthalmology Department, Central Children’s Hospital of Georgia, Tbilisi, Georgia
                [170 ]Division of Pediatric Hematology-Oncology, Department of Pediatrics, Cerrahpaşa Faculty of Medicine and Oncology Institute, Istanbul University, Istanbul, Turkey
                [171 ]St. Anne’s University Hospital Brno, Masaryk University, and International Clinical Research Center/St Anna University Hospital, Brno, Czech Republic
                [172 ]Dhaka Medical College Hospital, Dhaka, Bangladesh
                [173 ]Department of Ophthalmology, Postgraduate Medical Institute, Ameer-Ud-Din Medical College, Lahore General Hospital, Lahore, Pakistan
                [174 ]Angkor Hospital for Children, Krong Siem Reap, Cambodia
                [175 ]Duke Eye Center, Duke University Hospital, Durham, North Carolina
                [176 ]Sankara Nethralaya, Chennai, India
                [177 ]Department of Ophthalmology, Seoul National University Hospital, Seoul, Republic of Korea
                [178 ]Ocular Oncology Service, Department of Ophthalmology, Hacettepe University School of Medicine, Ankara, Turkey
                [179 ]Ocular Oncology Service, Department of Ophthalmology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
                [180 ]East Tallinn Central Hospital, Tallinn, Estonia
                [181 ]Oncologue Pédiatre Responsable d’Unité de Bangui, Bangui, Central African Republic
                [182 ]Children’s Ophthalmology Department, Children’s Hospital of Vilnius, University Hospital Santaros Clinic, Vilnius, Lithuania
                [183 ]Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa
                [184 ]Vitreo-Retina Research Unit, Department of Ophthalmology, Chulalongkorn University, Bangkok, Thailand
                [185 ]University Medical Center Hamburg-Eppendorf, Hamburg, Germany
                [186 ]Hong Kong Eye Hospital, Chinese University of Hong Kong, Hong Kong SAR, China
                [187 ]Perth Children’s Hospital, University of Western Australia, Perth, Western Australia, Australia
                [188 ]Clinical Center of Vojvodina, University Eye Clinic, Eye Research Foundation Vidar–Latinović, Novi Sad, Serbia
                [189 ]Division of Ophthalmology, Feinberg School of Medicine, Northwestern University, and Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois
                [190 ]John A. Burns School of Medicine, University of Hawaii, Honolulu, and University of Southern California Roski Eye Institute, Los Angeles
                [191 ]Division of Ophthalmology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
                [192 ]Phoenix Children’s Hospital, Phoenix, Arizona
                [193 ]Affiliated Hospital of Dali University, Dali City, China
                [194 ]Tilganga Institute of Ophthalmology, Kathmandu, Nepal
                [195 ]Singapore National Eye Center, Singapore, Singapore
                [196 ]Ophthalmology Department, Faculty of Medicine, Universidad de Chile, Santiago, Chile
                [197 ]University Clinics of Lubumbashi, University of Lubumbashi, Lubumbashi, Democratic Rrepublic of Congo
                [198 ]Pediatric Hematology/Oncology/Stem Cell Transplantation, Center for Global Health, Children’s Hospital Colorado, University of Colorado, Aurora
                [199 ]Department of Ophthalmology, Dr Soetomo General Hospital, Airlangga University, Surabaya, Indonesia
                [200 ]Okhmatdyt National Children’s Hospital, Kiev, Ukraine
                [201 ]Pediatric Hematology-Oncology Unit, Apollo Center for Advanced Pediatrics, Indraprastha Apollo Hospital, New Delhi, India
                [202 ]Sekuru Kaguvi Eye Unit, Parirenyatwa Group of Hospitals, Harare, Zimbabwe
                [203 ]National Center of Oncology and Hematology, Bishkek, Kyrgyzstan
                [204 ]University of Alabama at Birmingham, Birmingham
                [205 ]Ruharo Eye Centre, Ruharo Mission Hospital, Mbarara, Uganda
                [206 ]Scottish Livingstone Hospital, Molepolole, Botswana
                [207 ]Department of Ocular Oncology, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia
                [208 ]Department of Oncology, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
                [209 ]MAHAK Hematology Oncology Research Center, Mahak Hospital, Tehran, Iran
                [210 ]Department of Ophthalmology, Jimma University, Jimma, Ethiopia
                [211 ]Centre for Sight, New Delhi, India
                [212 ]Department of Ophthalmology, University of Padova, Padova, Italy
                [213 ]Sankara Eye Hospital, Bangalore, India
                [214 ]Kilimanjaro Christian Medical Centre, Moshi, Tanzania
                [215 ]Department of Pathology, Faculty of Medicine, University of Gezira, Wad Medani, Sudan
                [216 ]King Hussein Cancer Center, Amman, Jordan
                [217 ]Department of Ophthalmology, Amsterdam UMC, Amsterdam, the Netherlands
                [218 ]Hospital Infantil Dr Robert Reid Cabral, Santo Domingo, Dominican Republic
                [219 ]Service d’Oncologie Pédiatrique de l’Hôpital Aristide le Dantec, Dakar, Senegal
                [220 ]Ministry of Health, Lusaka, Zambia
                [221 ]Jules-Gonin Eye Hospital, Fondation Asile de Aveugles, University of Lausanne, Lausanne, Switzerland
                [222 ]Department of Ophthalmology, Lagos University Teaching Hospital, College of Medicine of the University of Lagos, Lagos, Nigeria
                [223 ]Abii Specialists Hospital, Bamenda, Cameroon
                [224 ]Aditya Jyot Eye Hospital, Mumbai, India
                [225 ]Lokmanya Tilak Municipal General Hospital and Medical College, Mumbai, India
                [226 ]N.N. Alexandrov National Cancer Centre of Belarus, Minsk, Belarus
                [227 ]Cheikh Anta Diop University, Le Dantec Hospital, Dakar, Senegal
                [228 ]Child Health Department, Faculty of Medicine, Diponegoro University, Semarang, Indonesia
                [229 ]Moscow Helmholtz Research Institute of Eye Diseases, Moscow, Russia
                [230 ]Ho Chi Minh Eye Hospital, Ho Chi Minh, Vietnam
                [231 ]Department of Ophthalmology, Calabar Children’s Eye Center, University of Calabar Teaching Hospital, Calabar Nigeria
                [232 ]Chittagong Eye Infirmary and Training Complex, Chittagong, Bangladesh
                [233 ]Arthur Davison Children’s Hospital, Ndola, Zambia
                [234 ]CHU Angondje Cancerologie, Libreville, Gabon
                [235 ]Sue Anschutz-Rodgers Eye Center, University of Colorado School of Medicine, Aurora
                [236 ]Komfo Anokye Teaching Hospital, Kumasi, Ghana
                [237 ]Clínica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile
                [238 ]National Ophthalmological Institute of Angola, Luanda, Angola
                [239 ]H M Diwan Eye Foundation, and Tata Medical Center, Kolkata, India
                [240 ]Department of Oncology, Yerevan State Medical University, and Pediatric Cancer and Blood Disorders Center of Armenia, Hematology Center after R. H. Yeolyan, Yerevan, Armenia
                [241 ]University of British Columbia, Vancouver, British Columbia, Canada
                [242 ]University Hospital Center Zagreb, Zagreb, Croatia
                [243 ]Vietnam National Institute of Ophthalmology, Ha Noi, Vietnam
                [244 ]Centre Hospitalier Universitaire de Kamenge, Bujumbura, Burundi
                [245 ]Department of Ophthalmology for Children and Adults, Second Faculty of Medicine, Charles University, and Motol University Hospital, Prague, Czech Republic
                [246 ]Fundacion Clinica Valle del Lili, Cali, Colombia
                [247 ]Head and Neck Tumors Department, SRI of Pediatric Oncology and Hematology, N.N. Blokhin Russian Cancer Research Center, Moscow, Russia
                [248 ]Russian Medical Academy of Postgraduate Education, Moscow, Russia
                [249 ]University Eye Hospital Ljubljana, University Medical Center Ljubljana, Ljubljana, Slovenia
                [250 ]Good Shepherd Hospital, Siteki, Swaziland
                [251 ]Sardjito Hospital, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
                [252 ]Hiwa Cancer Hospital, Sulaymaniyah, Iraq
                [253 ]Department of Ophthalmology, Eye and Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China
                [254 ]Department of Ophthalmology, Hospital Infantil de Mexico Federico Gómez, Mexico City, Mexico
                [255 ]Centre Hospitalier Universitaire Joseph Ravoahangy Andrianavalona, Antananarivo, Madagascar
                [256 ]Department of Oculoplasty and Ocular Oncology, Ispahani Islamia Eye Institute and Hospital, Dhaka, Bangladesh
                [257 ]Department of Ophthalmology, Davidoff Center for Oncology, Rabin Medical Center, Sackler School of Medicine, Tel Aviv University, Israel
                [258 ]School of Medicine and Dentistry, Korle-Bu Teaching Hospital, University of Ghana, Accra, Ghana
                [259 ]University of Pretoria, Pretoria, South Africa
                [260 ]Federal Medical Center, Yola, Nigeria
                [261 ]Nampula Central Hospital, Nampula, Mozambique
                [262 ]Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
                [263 ]Children’s Cancer Institute, American University of Beirut Medical Center, Beirut, Lebanon
                [264 ]NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital, and UCL Institute of Ophthalmology and London Retinoblastoma Service, Royal London Hospital, London, United Kingdom
                [265 ]Department of Ophthalmology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
                [266 ]Hospital Dr Manuel Ascencio Villarroel, Cochabamba, Bolivia
                [267 ]Pediatric Hemato-Oncology, Hospital Universitario Infantil La Paz, Madrid, Spain
                [268 ]Hospital Solca Quito, Quito, Ecuador
                [269 ]Mahosot Hospital, Vientiane, Laos
                [270 ]Department of Ophthalmology, Rasool Akram Hospital, Tehran, Iran
                [271 ]Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
                [272 ]National Institute of Ophthalmology, Dhaka, Bangladesh
                [273 ]East Timor Eye Program, Dili, Timor-Leste
                [274 ]Tata Memorial Hospital, Mumbai, India
                [275 ]Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania
                [276 ]Ophthalmology Department, Nouakchott Medical University, Nouakchott, Mauritania
                [277 ]Department of Ophthalmology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
                [278 ]Department of Ophthalmology, Faculty of Medicine, Universitas Indonesia, and Dr Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia
                [279 ]Casey Eye Institute, Oregon Health & Science University, Portland
                [280 ]Mulago National Referral Hospital, Kampala, Uganda
                [281 ]Department of Ophthalmology, University of Washington, Seattle
                [282 ]Centre for Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia
                [283 ]Children’s Mercy Hospital, Kansas City, Missouri
                [284 ]Department of Paediatrics and Child Health, University of the Free State, Bloemfontein, South Africa
                [285 ]BC Children’s Hospital, Vancouver, British Columbia, Canada
                [286 ]Pediatra Hemato-Oncologa, Instituto Oncologico del Oriente Boliviano, Santa Cruz de la Sierra, Bolivia
                [287 ]Henan Children’s Hospital, Affiliated Children’s Hospital of Zhengzhou University, Zhengzhou, China
                [288 ]Queen Sirikit National Institute of Child Health, Bangkok, Thailand
                [289 ]Department of Ophthalmic Oncology, National Cancer Center Hospital, Tokyo, Japan
                [290 ]Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University, Motol University Hospital, Prague, Czech Republic
                [291 ]Africa Institute of Tropical Ophthalmology, Bamako, Mali
                [292 ]Hospital Nacional Edgardo Rebagliati Martins, Lima, Perú
                [293 ]University Eye Clinic, Skopje, Macedonia
                [294 ]National Cancer Center, Dharmais Cancer Hospital, Jakarta, Indonesia
                [295 ]Ophthalmology Department, Federal University of São Paulo, São Paulo, Brazil
                [296 ]Kabgayi Eye Unit, Gitarama, Rwanda
                [297 ]Department of Pediatric Hematology-Oncology, Schneider Children’s Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
                [298 ]Pediatric Oncology Service, Gabriel Toure Hospital, Bamako, Mali
                [299 ]Department of Ophthalmology, Faculty of Medicine, Ocular Oncology Service, Istanbul University, Istanbul, Turkey
                [300 ]Université Adam Barka, Abeche, Chad
                [301 ]Division of Pediatric Hematology-Oncology, Department of Pediatrics, Ankara University, Ankara, Turkey
                [302 ]Department of Ophthalmology, Aarhus University Hospital, Aarhus, Denmark
                [303 ]National Cancer Center of Uzbekistan, Tashkent, Uzbekistan
                [304 ]Children’s Clinical University Hospital, Riga, Latvia
                [305 ]Department of Ophthalmology, Medical University of Graz, Graz, Austria
                [306 ]Jos University Teaching Hospital, Jos, Nigeria
                [307 ]National Eye Center Kaduna, Kaduna, Nigeria
                [308 ]Department of Paediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, China
                [309 ]Department of Surgery, St Jude Children’s Research Hospital, Memphis, Tennessee
                [310 ]Department of Ophthalmology, Chiang Mai University, Chiang Mai, Thailand
                [311 ]Department of Ophthalmology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
                [312 ]Department of Pediatric Ophthalmology, Guangzhou Children’s Hospital and Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
                [313 ]Kunming Children’s Hospital, Kunming, China
                [314 ]State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
                [315 ]Service d’Ophtalmologie, Cliniques Universitaires de Kinshasa, Université de Kinshasa, Kinshasa, Democratic Republic of Congo
                [316 ]Armed Forces Institute of Ophthalmology, Rawalpindi, Pakistan
                [317 ]S.Fyodorov Eye Microsurgery Federal State Institution, Moscow, Russia
                [318 ]Assistante Hospitalo Universitaire, Faculte de Medecine de Nouakchott Medecin Oncopediatre, Center National d’Oncologie, Nouakchott, Mauritania
                [319 ]Department of Ophthalmology, Beijing Children’s Hospital, Capital Medical University, Beijing, China
                [320 ]Department of Ophthalmology, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
                [321 ]Ophthalmology Department, Great Ormond Street Hospital, London, United Kingdom
                Author notes
                Article Information
                Group Information:
                Accepted for Publication:
                Corresponding Author: Ido Didi Fabian, MD, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom ( didi@ 123456didifabian.com ).
                Open Access: CC-BY License JAMA Oncology
                Published Online:10.1001/jamaoncol.2019.6716
                The Global Retinoblastoma Study Group Authors:
                Affiliations of The Global Retinoblastoma Study Group Authors:
                Author Contributions:
                Study concept and design:
                Acquisition, analysis, or interpretation of data:
                Drafting of the manuscript:
                Critical revision of the manuscript for important intellectual content:
                Statistical analysis:
                Conflict of Interest Disclosures: Pediatric Retina Disease, Second Edition
                Funding/Support:
                Role of the Funder/Sponsor:
                Additional Contributions:
                Additional Information:
                Article
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                10.1001/jamaoncol.2019.6716
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                Copyright 2020 Global Retinoblastoma Study Group. JAMA Oncology.

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