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. 2020 Feb 27;6(5):1–12. doi: 10.1001/jamaoncol.2019.6716

Global Retinoblastoma Presentation and Analysis by National Income Level

Global Retinoblastoma Study Group, Ido Didi Fabian 1,2,✉, Elhassan Abdallah 3, Shehu U Abdullahi 4, Rula A Abdulqader 5, Sahadatou Adamou Boubacar 6, Dupe S Ademola-Popoola 7, Adedayo Adio 8, Armin R Afshar 9, Priyanka Aggarwal 10, Ada E Aghaji 11, Alia Ahmad 12, Marliyanti N R Akib 13, Lamis Al Harby 14, Mouroge H Al Ani 15, Aygun Alakbarova 16, Silvia Alarcón Portabella 17, Safaa A F Al-Badri 18, Ana Patricia A Alcasabas 19, Saad A Al-Dahmash 20, Amanda Alejos 21, Ernesto Alemany-Rubio 22, Amadou I Alfa Bio 23, Yvania Alfonso Carreras 24, Christiane Al-Haddad 25, Hamoud H Y Al-Hussaini 26, Amany M Ali 27, Donjeta B Alia 28, Mazin F Al-Jadiry 18, Usama Al-Jumaly 29, Hind M Alkatan 20, Charlotta All-Eriksson 30, Ali A R M Al-Mafrachi 31, Argentino A Almeida 32, Khalifa M Alsawidi 33, Athar A S M Al-Shaheen 5, Entissar H Al-Shammary 34, Primawita O Amiruddin 35, Romanzo Antonino 36, Nicholas J Astbury 1, Hatice T Atalay 37, La-ongsri Atchaneeyasakul 38, Rose Atsiaya 39, Taweevat Attaseth 40, Than H Aung 41, Silvia Ayala 42, Baglan Baizakova 43, Julia Balaguer 44, Ruhengiz Balayeva 16, Walentyna Balwierz 45, Honorio Barranco 44, Covadonga Bascaran 1, Maja Beck Popovic 46, Raquel Benavides 47, Sarra Benmiloud 48, Nissrine Bennani Guebessi 49, Rokia C Berete 50, Jesse L Berry 51, Anirban Bhaduri 52, Sunil Bhat 53, Shelley J Biddulph 54, Eva M Biewald 55, Nadia Bobrova 56, Marianna Boehme 55, HC Boldt 57, Maria Teresa B C Bonanomi 58, Norbert Bornfeld 55, Gabrielle C Bouda 59, Hédi Bouguila 60, Amaria Boumedane 61, Rachel C Brennan 62, Bénédicte G Brichard 63, Jassada Buaboonnam 38, Patricia Calderón-Sotelo 64, Doris A Calle Jara 65, Jayne E Camuglia 66, Miriam R Cano 67, Michael Capra 68, Nathalie Cassoux 69, Guilherme Castela 70, Luis Castillo 71, Jaume Català-Mora 72, Guillermo L Chantada 72,73,74, Shabana Chaudhry 75, Sonal S Chaugule 76, Argudit Chauhan 77, Bhavna Chawla 78, Violeta S Chernodrinska 79, Faraja S Chiwanga 80, Tsengelmaa Chuluunbat 81, Krzysztof Cieslik 82, Ruellyn L Cockcroft 83, Codruta Comsa 84, Zelia M Correa 85, Maria G Correa Llano 72, Timothy W Corson 86, Kristin E Cowan-Lyn 87, Monika Csóka 88, Xuehao Cui 89, Isac V Da Gama 90, Wantanee Dangboon 91, Anirban Das 92, Sima Das 93, Jacquelyn M Davanzo 94, Alan Davidson 95, Patrick De Potter 63, Karina Q Delgado 96, Hakan Demirci 97, Laurence Desjardins 98, Rosdali Y Diaz Coronado 99, Helen Dimaras 100, Andrew J Dodgshun 101, Craig Donaldson 102, Carla R Donato Macedo 103, Monica D Dragomir 84, Yi Du 104, Magritha Du Bruyn 105, Kemala S Edison 106, I Wayan Eka Sutyawan 107, Asmaa El Kettani 49, Amal M Elbahi 33, James E Elder 108,109, Dina Elgalaly 110, Alaa M Elhaddad 110, Moawia M Ali Elhassan 111, Mahmoud M Elzembely 27, Vera A Essuman 112, Ted Grimbert A Evina 113, Zehra Fadoo 114, Adriana C Fandiño 73, Mohammad Faranoush 115, Oluyemi Fasina 116, Delia D P G Fernández 117, Ana Fernández-Teijeiro 118, Allen Foster 1, Shahar Frenkel 119, Ligia D Fu 120, Soad L Fuentes-Alabi 121, Brenda L Gallie 100, Moira Gandiwa 122, Juan L Garcia 123, David García Aldana 124, Pascale Y Gassant 24, Jennifer A Geel 125, Fariba Ghassemi 126, Ana V Girón 21, Zelalem Gizachew 127, Marco A Goenz 121, Aaron S Gold 128, Maya Goldberg-Lavid 129, Glen A Gole 66, Nir Gomel 130, Efren Gonzalez 131, Graciela Gonzalez Perez 132, Liudmira González-Rodríguez 22, Henry N Garcia Pacheco 133, Jaime Graells 134, Liz Green 135, Pernille A Gregersen 136, Nathalia D A K Grigorovski 137, Koffi M Guedenon 138, D Sanjeeva Gunasekera 139, Ahmet K Gündüz 140, Himika Gupta 141, Sanjiv Gupta 142, Theodora Hadjistilianou 143, Patrick Hamel 144, Syed A Hamid 145, Norhafizah Hamzah 146, Eric D Hansen 147, J William Harbour 148, M Elizabeth Hartnett 147, Murat Hasanreisoglu 37, Sadiq Hassan 4, Shadab Hassan 149, Stanislava Hederova 150, Jose Hernandez 151, Lorelay Marie Carcamo Hernandez 96, Laila Hessissen 152, Diriba F Hordofa 153, Laura C Huang 154, G B Hubbard 155, Marlies Hummlen 156, Kristina Husakova 150, Allawi N Hussein Al-Janabi 157, Russo Ida 36, Vesna R Ilic 158, Vivekaraj Jairaj 159, Irfan Jeeva 114, Helen Jenkinson 160, Xunda Ji 89, Dong Hyun Jo 161, Kenneth P Johnson 162, William J Johnson 163, Michael M Jones 102, Theophile B Amani Kabesha 164, Rolande L Kabore 59, Swathi Kaliki 165, Abubakar Kalinaki 166, Mehmet Kantar 167, Ling-Yuh Kao 168, Tamar Kardava 169, Rejin Kebudi 170, Tomas Kepak 171, Naama Keren-Froim 129, Zohora J Khan 172, Hussain A Khaqan 173, Phara Khauv 174, Wajiha J Kheir 175, Vikas Khetan 176, Alireza Khodabande 126, Zaza Khotenashvili 169, Jonathan W Kim 51, Jeong Hun Kim 177, Hayyam Kiratli 178, Tero T Kivelä 179, Artur Klett 180, Jess Elio Kosh Komba Palet 181, Dalia Krivaitiene 182, Mariana Kruger 183, Kittisak Kulvichit 184, Mayasari W Kuntorini 35, Alice Kyara 80, Eva S Lachmann 185, Carol P S Lam 186, Geoffrey C Lam 187, Scott A Larson 57, Slobodanka Latinović 188, Kelly D Laurenti 189, Bao Han A Le 190, Karin Lecuona 191, Amy A Leverant 192, Cairui Li 193, Ben Limbu 194, Quah Boon Long 195, Juan P López 196, Robert M Lukamba 197, Livia Lumbroso 98, Sandra Luna-Fineman 198, Delfitri Lutfi 199, Lesia Lysytsia 200, George N Magrath 163, Amita Mahajan 201, Abdul Rahim Majeed 135, Erika Maka 88, Mayuri Makan 202, Emil K Makimbetov 203, Chatonda Manda 122, Nieves Martín Begue 17, Lauren Mason 204, John O Mason III 204, Ibrahim O Matende 39, Miguel Materin 175, Clarissa C D S Mattosinho 137, Marchelo Matua 205, Ismail Mayet 54, Freddy B Mbumba 206, John D McKenzie 108,207, Aurora Medina-Sanson 208, Azim Mehrvar 209, Aemero A Mengesha 210, Vikas Menon 211, Gary John V D Mercado 19, Marilyn B Mets 189, Edoardo Midena 212, Divyansh K C Mishra 213, Furahini G Mndeme 214, Ahmed A Mohamedani 215, Mona T Mohammad 216, Annette C Moll 217, Margarita M Montero 218, Rosa A Morales 64, Claude Moreira 219, Prithvi Mruthyunjaya 154, Mchikirwa S Msina 214, Gerald Msukwa 122, Sangeeta S Mudaliar 141, Kangwa I Muma 220, Francis L Munier 221, Gabriela Murgoi 84, Timothy G Murray 128, Kareem O Musa 222, Asma Mushtaq 12, Hamzah Mustak 191, Okwen M Muyen 223, Gita Naidu 54, Akshay Gopinathan Nair 224,225, Larisa Naumenko 226, Paule Aïda Ndoye Roth 227, Yetty M Nency 228, Vladimir Neroev 229, Hang Ngo 230, Rosa M Nieves 218, Marina Nikitovic 158, Elizabeth D Nkanga 231, Henry Nkumbe 113, Murtuza Nuruddin 232, Mutale Nyaywa 233, Ghislaine Obono-Obiang 234, Ngozi C Oguego 11, Andrzej Olechowski 82, Scott C N Oliver 235, Peter Osei-Bonsu 236, Diego Ossandon 237, Manuel A Paez-Escamilla 148, Halimah Pagarra 13, Sally L Painter 160, Vivian Paintsil 236, Luisa Paiva 238, Bikramjit P Pal 239, Mahesh Shanmugam Palanivelu 213, Ruzanna Papyan 240, Raffaele Parrozzani 212, Manoj Parulekar 160, Claudia R Pascual Morales 151, Katherine E Paton 241, Katarzyna Pawinska-Wasikowska 45, Jacob Pe'er 119, Armando Peña 120, Sanja Perić 242, Chau T M Pham 243, Remezo Philbert 244, David A Plager 86, Pavel Pochop 245, Rodrigo A Polania 246, Vladimir G Polyakov 247,248, Manca T Pompe 249, Jonathan J Pons 250, Daphna Prat 2, Vireak Prom 176, Ignatius Purwanto 251, Ali O Qadir 252, Seema Qayyum 12, Jiang Qian 253, Ardizal Rahman 106, Salman Rahman 9, Jamalia Rahmat 146, Purnima Rajkarnikar 194, Rajesh Ramanjulu 213, Aparna Ramasubramanian 77, Marco A Ramirez-Ortiz 254, Léa Raobela 255, Riffat Rashid 256, M Ashwin Reddy 14, Ehud Reich 257, Lorna A Renner 258, David Reynders 259, Dahiru Ribadu 260, Mussagy M Riheia 261, Petra Ritter-Sovinz 262, Duangnate Rojanaporn 40, Livia Romero 134, Soma R Roy 232, Raya H Saab 263, Svetlana Saakyan 229, Ahmed H Sabhan 18, Mandeep S Sagoo 264, Azza M A Said 265, Rohit Saiju 194, Beatriz Salas 266, Sonsoles San Román Pacheco 267, Gissela L Sánchez 268, Phayvanh Sayalith 269, Trish A Scanlan 80, Amy C Schefler 42, Judy Schoeman 259, Ahad Sedaghat 270, Stefan Seregard 30, Rachna Seth 271, Ankoor S Shah 131, Shawkat A Shakoor 272, Manoj K Sharma 273, Sadik T Sherief 127, Nandan G Shetye 274, Carol L Shields 275, Sorath Noorani Siddiqui 149, Sidi Sidi Cheikh 276, Sónia Silva 70, Arun D Singh 94, Niharika Singh 176, Usha Singh 277, Penny Singha 91, Rita S Sitorus 278, Alison H Skalet 279, Hendrian D Soebagjo 199, Tetyana Sorochynska 56, Grace Ssali 280, Andrew W Stacey 281, Sandra E Staffieri 108,282, Erin D Stahl 283, Christina Stathopoulos 221, Branka Stirn Kranjc 249, David K Stones 284, Caron Strahlendorf 285, Maria Estela Coleoni Suarez 286, Sadia Sultana 256, Xiantao Sun 287, Meryl Sundy 279, Rosanne Superstein 144, Eddy Supriyadi 251, Supawan Surukrattanaskul 288, Shigenobu Suzuki 289, Karel Svojgr 290, Fatoumata Sylla 291, Gevorg Tamamyan 240, Deborah Tan 195, Alketa Tandili 28, Fanny F Tarrillo Leiva 292, Maryam Tashvighi 209, Bekim Tateshi 293, Edi S Tehuteru 294, Luiz F Teixeira 103,295, Kok Hoi Teh 146, Tuyisabe Theophile 296, Helen Toledano 297, Doan L Trang 243, Fousseyni Traoré 298, Sumalin Trichaiyaporn 288, Samuray Tuncer 299, Harba Tyau-Tyau 300, Ali B Umar 4, Emel Unal 301, Ogul E Uner 155, Steen F Urbak 302, Tatiana L Ushakova 247, 248, Rustam H Usmanov 303, Sandra Valeina 304, Milo van Hoefen Wijsard 217, Adisai Varadisai 184, Liliana Vasquez 292, Leon O Vaughan 87, Nevyana V Veleva-Krasteva 79, Nishant Verma 142, Andi A Victor 278, Maris Viksnins 304, Edwin G Villacís Chafla 65, Vicktoria Vishnevskia-Dai 2, Tushar Vora 274, Antonio E Wachtel 99, Werner Wackernagel 305, Keith Waddell 205, Patricia D Wade 306, Amina H Wali 307, Yi-Zhuo Wang 308, Avery Weiss 281, Matthew W Wilson 309, Amelia D C Wime 238, Atchareeya Wiwatwongwana 310, Damrong Wiwatwongwana 310, Charlotte Wolley Dod 17, Phanthipha Wongwai 311, Daoman Xiang 312, Yishuang Xiao 313, Jason C Yam 186, Huasheng Yang 314, Jenny M Yanga 315, Muhammad A Yaqub 316, Vera A Yarovaya 317, Andrey A Yarovoy 317, Huijing Ye 314, Yacoub A Yousef 216, Putu Yuliawati 107, Arturo M Zapata López 99, Ekhtelbenina Zein 318, Chengyue Zhang 319, Yi Zhang 308, Junyang Zhao 319, Xiaoyu Zheng 320, Katsiaryna Zhilyaeva 226, Nida Zia 145, Othman A O Ziko 265, Marcia Zondervan 1, Richard Bowman 1,321
PMCID: PMC7047856  PMID: 32105305

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.

Introduction

Retinoblastoma, the most common eye cancer of childhood, is fatal if left untreated. Prognosis of patients with retinoblastoma in high-income countries (HICs) has improved over the past 50 years, now reaching a near 100% disease-free survival rate.1,2,3 This is attributed to several factors, including (1) creation of specialized referral centers, (2) decoding of the genetic basis of the disease, (3) formation of screening programs, and (4) the introduction of chemotherapy.4 In HICs, retinoblastoma is a curable disease, and attention has now shifted to eye salvage5,6 and improvement of quality of life.7 In low- and middle-income countries (LMICs), where more than 80% of global retinoblastoma cases arise, the prognosis is poor, and it is assumed that this is because of delayed diagnosis and treatment.8,9,10 Publications from LMICs are scarce, and many countries do not report their retinoblastoma data.11 The stage of retinoblastoma at the time of diagnosis in low-income, middle-income, and high-income countries has not been surveyed globally. This information is important for policy and health care planning at national and international levels.

The objectives of this study are to (1) report the stage at diagnosis in a large global sample of patients with retinoblastoma, (2) examine associations between clinical variables at presentation and national-income level, and (3) investigate risk factors for advanced disease at diagnosis.

Methods

This study originated from a consortium of retinoblastoma treatment centers in 8 countries on 3 continents.12 From June 2017 through December 2018, all known retinoblastoma treatment centers across the world were contacted by means of personal communications, presentations at scientific conferences, and linking to professional societies in the fields of ophthalmology and oncology to form a global network. All centers involved in the diagnosis and treatment of patients with retinoblastoma, at least by means of enucleation, were eligible to participate.

Study Design

This study adheres to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.13 It was a 1-year cross-sectional analysis that included all treatment-naive patients with retinoblastoma who presented to participating centers from January 1, 2017, to December 31, 2017, and who were treated or offered treatment for retinoblastoma. A predesigned form was used for data collection (eTable 1 in the Supplement). The data collected included country of residence, sex, first ocular symptom as noted by parents, age at first indication of symptom, age and ocular indication at presentation to the retinoblastoma treatment center, laterality, familial history of retinoblastoma, staging according to the American Joint Committee on Cancer Staging Manual, Eighth Edition14 and the International Retinoblastoma Staging System,15 and primary treatment. Data on country of residence, sex, and laterality were minimum criteria for patient enrollment. The staging classifications were simplified to include only the major subcategories (eTable 2 in the Supplement). For the primary tumor site (cT), the eye with the more advanced disease was used for analysis. Completed forms were electronically uploaded onto a secure server, after which a data quality assurance process was performed (eMethods in the Supplement).

The study was approved by the institutional review board at the London School of Hygiene & Tropical Medicine, which granted a waiver of patient informed consent. Participating centers applied for and received ethics clearance in their countries according to local institutional guidelines.

Statistical Analysis

All analyses were performed using R software, version 3.5.2 (R Foundation for Statistical Computing), and IBM SPSS Statistics, version 25.0 (IBM Corp). The crude birth rate, country population size, and country classification by national income level were obtained from the 2017 World Population Prospects.16 The predicted number of new patients with retinoblastoma per country was calculated as follows: [country population × crude birth rate/1000/17 000], and predicted number per national income level was the sum result of all countries at the same level.

Unless otherwise indicated, summary statistics are presented as median and interquartile range (25%-75%). The t test was used to compare means of normally distributed continuous variables, Fisher exact and Pearson χ2 tests were used to compare categorical variables, Spearman rank correlation test was used for nonnormal continuous and ordinal variables, and the Cochran-Armitage test17,18 was used to test for trend in the proportions of patients with a given parameter across the income levels. Binomial logistic regression was used to model the effect of income level (upper-middle–income level and high-income level combined), presentation age (grouped by tertiles), familial retinoblastoma history, sex, and bilaterality, on the likelihood of children having advanced disease (cT4) at presentation. An α level of .05 and 2-tailed P values were used to determine statistical significance.

Results

The study sample included 4351 treatment-naive patients with retinoblastoma residing in 153 countries (Figure). The data analyzed by national income level are shown in Table 1. Country-level and continent-level data are shown at http://globalretinoblastoma.org (password: Ret2017).

Figure. Cohort Recruitment Flowchart.

Figure.

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aPatients from 23 countries with no retinoblastoma centers were treated outside of their country of residence.

bInclusion criteria included reporting of country of residence, sex, and laterality. Patients for whom 1 or more of these parameters were not available were not included in the analytic sample.

Table 1. Clinical Characteristics at Presentation of 4351 New Patients With Retinoblastoma Diagnosed in 2017.

Parameter National Income Level, No. (% within the national income level) [% within the evaluated parameter] Total, No. (%) Significance P Value
Low Lower-Middle Upper-Middle High
Age at diagnosis, median (IQR), mo
Total sample 30.5 (18.3-45.9) 24.4 (12.2-37.3) 20.7 (10.1-33.8) 14.0 (6.2-26.6) 23.5 (11.2-36.5) ρ: −0.22 <.001a
Unilateral 35.0 (22.2-48.0) 29.1 (18.1-42.9) 25.5 (12.9-37.6) 19.7 (9.0-32.4) 27.1 (15.0-41.0)
Bilateral 22.9 (11.8-32.8) 14.4 (8.0-25.8) 11.4 (6.0-21.0) 8.1 (3.7-15.8) 12.3 (6.1-24.3)
Reported cases, No. (%) 524/533 (98.3) 1909/1940 (98.4) 1192/1212 (98.3) 664/666 (99.7) 4289/4351 (98.6)
Laterality at diagnosisb
Unilateral 408 (76.5) [13.6] 1325 (68.3) [44.0] 847 (69.9) [28.1] 430 (64.6) [14.3] 3010/4351 (69.2) NA <.001c
Bilateral 125 (23.5) [9.3] 615 (31.7) [45.9] 365 (30.1) [27.2] 236 (35.4) [17.6] 1341/4351 (30.8)
Familial history of retinoblastoma
No 467 (96.9) [11.6] 1805 (96.0) [44.9] 1141 (95.5) [28.4] 603 (91.6) [15.0] 4016/4215 (95.3) z score: −4.3, dim: 4 <.001d
Yes 15 (3.1) [7.5] 75 (4.0) [37.7] 54 (4.5) [27.1] 55 (8.4) [27.6] 199/4215 (4.7)
Total, No. (%) 482/533 (90.4) 1880/1940 (96.9) 1195/1212 (98.6) 658/666 (98.8) 4215/4351 (96.9)
Primary tumor
cT1 5 (1.0) [1.8] 96 (5.1) [35.3] 67 (6.1) [24.6] 104 (15.9) [38.2] 272/4114 (6.7) z score: 22.3, dim: 4 <.001e
cT2 62 (12.6) [4.9] 406 (21.7) [31.8] 482 (44.1) [37.8] 326 (49.7) [25.5] 1276/4114 (31.0)
cT3 209 (42.6) [10.8] 1013 (54.1) [52.4] 488 (44.6) [25.2] 223 (34.0) [11.5] 1933/4114 (47.0)
cT4 215 (43.8) [34.0] 359 (19.2) [56.7] 56 (5.1) [8.8] 3 (0.4) [0.4] 633/4114 (15.4)
Total, No. (%) 491/533 (92.1) 1874/1940 (96.6) 1093/1212 (90.2) 656/666 (98.5) 4114/4351 (94.6)
Regional lymph node
NX 105 (20.7) [12.6] 350 (18.4) [42.1] 267 (22.2) [32.1] 109 (16.4) [13.1] 831/4281 (19.4) z score: 8.3, dim: 4 <.001f
N0 360 (71.0) [10.9] 1475 (77.3) [44.7] 912 (75.9) [27.6] 556 (83.6) [16.8] 3303/4281 (77.2)
N1 42 (8.3) [28.6] 82 (4.3) [55.8] 23 (1.9) [15.6] 0 147/4281 (3.4)
Total, No. (%) 507/533 (95.1) 1907/1940 (98.3) 1202/1212 (99.2) 665/666 (99.8) 4281/4352 (98.4)
Distant metastasis
M0 404 (81.1) [10.2] 1749 (91.8) [44.1] 1147 (95.2) [28.9] 664 (99.7) [16.8] 3964/4275 (92.7) z score: 11.9, dim: 4 <.001g
cM1 65 (13.1) [30.4] 110 (5.8) [51.4] 39 (3.2) [18.2] 0 214/4275 (5.0)
pM1 29 (5.8) [29.9] 47 (2.5) [48.5] 19 (1.6) [19.6] 2 (0.3) [2.1] 97/4275 (2.3)
Total, No. (%) 498/533 (89.1) 1906/1940 (98.2) 1205/1212 (99.4) 666/666 (100) 4275/4351 (98.3)
Hereditary trait
HX 360 (72.7) [14.2] 1211 (63.8) [47.9] 736 (61.6) [29.1] 221 (33.4) [8.7] 2528/4250 (59.5) NA NA
H0 0 44 (2.3) [17.3] 59 (4.9) [23.2] 151 (22.8) [59.4] 254/4250 (6.0)
H1 135 (27.3) [9.2] 643 (33.9) [43.8] 400 (33.5) [27.2] 290 (43.8) [19.8] 1468/4250 (34.5)
Total, No. (%) 495/533 (92.9) 1898/1940 (97.8) 1195/1212 (98.6) 662/666 (99.4) 4250/4351 (97.7)
Extraocular retinoblastoma
No 265 (50.9) [7.8] 1393 (73.0) [41.3] 1062 (88.0) [31.5] 656 (98.5) [19.4] 3376/4302 (78.5) z score: 21.8, dim: 4 <.001h
Yes 256 (49.1) [27.6] 515 (27.0) [55.6] 145 (12.0) [15.7] 10 (1.5) [1.1] 926/4302 (21.5)
Total, No. (%) 521/533 (97.7) 1908/1940 (98.4) 1207/1212 (99.6) 666/666 (100) 4302/4351 (98.9)
International Retinoblastoma Staging System
Stage 0 44 (8.7) [3.0] 459 (24.2) [31.3] 585 (48.8) [39.9] 378 (56.8) [25.8] 1466/4264 (34.4) NA NA
Stage I 170 (33.8) [1.0] 816 (43.0) [47.9] 444 (37.0) [26.1] 272 (40.8) [16.0] 1702/4264 (39.9)
Stage II 58 (11.5) [27.2] 111 (5.9) [52.1] 40 (3.3) [18.8] 4 (0.6) [1.9] 213/4264 (5.0)
Stage III 101 (20.1) [26.1] 242 (12.8) [62.5] 41 (3.4) [10.6] 3 (0.5) [0.7] 387/4264 (9.1)
Stage IV 94 (18.7) [29.9] 157 (8.3) [50.0] 60 (5.0) [19.1] 3 (0.5) [1.0] 314/4264 (7.4)
NA 36 (7.2) [19.8] 111 (5.9) [61.0] 29 (2.4) [15.9] 6 (0.9) [3.3] 182/4264 (4.3)
Total, No. (%) 503/533 (94.4) 1896/1940 (97.7) 1199/1212 (98.9) 666/666 (100) 4264/4351 (98.0)
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Abbreviations: IQR, interquartile range; NA, not applicable.

a

Spearman rank correlation.

b

Inclusion criteria: 100% reporting.

c

Fisher exact test for proportion of bilateral cases.

d

Cochran-Armitage test for proportion of familial history of retinoblastoma.

e

Cochran-Armitage test for proportion of cT3 or greater.

f

Cochran-Armitage test for proportion of cases with lymph node involvement.

g

Cochran-Armitage test for proportion of cases with distant metastasis.

h

Cochran-Armitage test for proportion of cases with extraocular disease.

Geographic and Socioeconomic Characteristics

More than half (2276 [52.3%]) of the patients were from Asia, 1024 (23.5%) were from Africa, 522 (12.0%) were from Europe, 512 (11.8%) were from the Americas, and 17 (0.4%) were from Oceania. Of all patients, 533 (12.3%) came from low-income countries (LICs), 1940 (44.6%) from lower-middle, 1212 (27.9%) from upper-middle, and 666 (15.3%) from HICs.

Completeness of Data

For 4116 (94.6%) of the study patients, data were reported on each study parameter, except for age at first ocular symptom of retinoblastoma (2175 [50.0%]; not included in the analysis). Analysis by national income level showed that reporting was nearly complete (≥98.5%) for patients from high-income and upper-middle–income countries, and more than 94.1% and 89.1% for patients from lower-middle–income countries and LICs, respectively.

Symptoms Leading to Referral

The most common first symptom of disease was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]), with a further 162 (3.9%) patients having a combination of leukocoria and strabismus (eTable 3 in the Supplement). Proptosis was reported in 309 (7.4%) patients. At least 1 symptom of advanced disease (ie, proptosis, swollen eyelids, red eye) was reported in 487 (11.7%) patients. A higher income level was associated with a lower proportion of patients with symptoms of advanced disease (z score = 10.9, dim = 4; P < .001; additional analysis is provided in eTable 4 in the Supplement).

Symptoms at Time of Diagnosis at Retinoblastoma Centers

Of all patients, 2998 (70.4%) presented with either leukocoria, strabismus, or a combination of these symptoms (eTable 3 in the Supplement). In LICs, combinations of proptosis, red eye, orbital cellulitis, and extraocular retinoblastoma (ie, advanced disease) were present in 248 (46.7%) patients. Analysis of patients who had only leukocoria and/or strabismus (ie, early disease) as the symptoms noticed by the parents, but who presented to retinoblastoma treatment centers with symptoms of advanced disease, showed a significantly larger proportion coming from LICs (z score = 18.4, dim = 4; P < .001; additional analysis is provided in eTable 4 in the Supplement).

Age at Diagnosis

The overall median age at diagnosis was 23.5 months (interquartile range [IQR], 11.2-36.5 months; Table 1). The median age at diagnosis of patients from LICs was 30.5 months (IQR, 18.3-45.9 months) compared with 14.0 months (IQR, 6.2-26.6 months) for patients from HICs. There was a significant association between presentation age and national income level, with children in LMICs presenting at an older age (eTable 5 in the Supplement).

Tumor Staging

Globally, the most common cTNM stages were cT3 (n = 1933 of 4114 [47.0%]), N0 (n = 3303 of 4281 [77.2%]), and M0 (n = 3964 of 4275 [92.7%]) (Table 1). Extraocular retinoblastoma at time of diagnosis was reported in 926 of 4302 (21.5%) patients (256 [49.1%] in LICs vs 10 [1.5%] in HICs). Distant metastases were reported in 94 (18.9%), 157 (8.3%), 58 (4.8%), and 2 (0.3%) patients from low, lower-middle, upper-middle, and high income–level countries, respectively (z score = 11.9, dim = 4; P < .001). Higher economic grouping was associated with higher proportions of intraocular and earlier stage disease at diagnosis (Table 1).

Risk Factors for Advanced Disease at Time of Diagnosis

Sex (χ21 = 1.016; P = .31), bilaterality (χ21 = 0.830; P = .36) and familial history of retinoblastoma (χ21 = 2.269; P = .13) were found to be nonsignificant factors for the prediction of cT4 category (extraocular retinoblastoma) and hence were removed from the model. On logistic regression, low-income level and older presentation age were found to be independent and significant predictive factors for advanced disease (Table 2).

Table 2. Logistic Regression Analysis: Predictors of Advanced Disease at Presentationa,b.

Variable B (SE) Corrected P Value Odds Ratio (95% CI)
Income level
Low vs (upper-middle + high) 2.886 (0.166) <.001 17.92 (12.94-24.80)
Low-middle vs (upper-middle + high) 1.748 (0.148) <.001 5.74 (4.30-7.68)
Age at diagnosis
14.27-31.20 mo 1.343 (0.167) <.001 3.83 (2.76-5.31)
>31.20 mo 2.026 (0.160) <.001 7.58 (5.54-10.38)
Constant −4.602 (0.190) <.001 0.01
Open in a new tab
a

The logistic regression model was statistically significant (χ24 = 727.27; P < .001). The model explained 28.5% (Nagelkerke R2) of the variance and correctly classified 85.1% of cases. Area under the curve was 0.813.

b

Advanced disease is defined as cT4.

Familial History and Bilateral Retinoblastoma

Familial history of retinoblastoma was reported in 199 of 4215 (4.7%) patients (15 [3.1%], 75 [4.0%], 54 [4.5%], and 55 [8.4%] patients from low, lower-middle, upper-middle, and high income–level countries, respectively). Bilateral disease at time of diagnosis was seen in 1341 of 4351 (30.8%) patients (125 [23.5%], 615 [31.7%], 365 [30.1%], and 236 [35.4%] patients from low, lower-middle, upper-middle, and high income–level countries, respectively) (Table 1). Significantly more familial (z score = −4.3, dim = 4; P < .001) and, independently, more bilateral cases were seen in HICs compared with LICs.

Diagnostic Facilities and Treatment Modalities

The available diagnostic and treatment modalities are shown in eTable 6 in the Supplement. The majority of patients (4201 [96.6%]) were diagnosed in a center that contained resources for computed tomography and/or magnetic resonance imaging. A histopathology service was available for 4236 (97.4%) participants, and intravenous chemotherapy for 4263 (98.0%).

Global Magnitude of Retinoblastoma and Representativeness of the Study

Given that the mean age at the time of diagnosis was approximately 2 years old, the 2015 birth rate data were used for calculation of the number of new retinoblastoma cases.16 According to these data, the predicted annual number of new retinoblastoma cases worldwide ranged from 7752 to 8914. Using an average incidence figure of 1 of 17 000 live births, capture rates were 88.2%, 56.5%, 48.7%, and 39.9% of expected cases from high, upper-middle, lower-middle, and low-income countries, respectively. No data were received from 65 countries and principalities, mainly with small populations; the estimated number of missing cases from these countries was 46.

Discussion

Findings of this study show a large disparity in the presentation patterns of retinoblastoma between HICs and LMICs. A total of 666 children were from HICs, 99% of whom had at the time of diagnosis a tumor confined to the eye and thus a favorable prognosis. In comparison, of the 3685 patients from LMICs, 25% were diagnosed with tumor spread beyond the globe, for which the prognosis is much worse.19,20 It is likely that the real gap in the pattern of retinoblastoma presentation is even wider owing to unreported patients in LICs who never arrived at a retinoblastoma treatment center and for whom death from metastatic disease is inevitable.

Late cancer diagnosis, also in the pediatric population, is a major issue in LMICs.21,22,23,24,25 This study confirms this finding for retinoblastoma, which, if detected early, can be cured. These findings are consistent with a recent study of global disease burden that found that cancer among 0- to 4-year-olds accounts for 37% of the global disease-adjusted life year; this proportional burden is greater in LMICs.26

The factors causing delay in retinoblastoma diagnosis and treatment in LMICs are beyond the scope of this study. However, the findings here suggest that late recognition of signs of retinoblastoma, as well as delay in reaching a dedicated retinoblastoma treatment center once ocular symptoms have been detected, likely play a role, and both factors are associated with national income level. These findings indicate clinically significant progression of signs between parental detection and presentation to a specialist center in LMICs. Earlier recognition of leukocoria or strabismus and urgent referral for diagnosis is very important if children are to receive treatment before extraocular spread occurs.

A familial history of retinoblastoma followed the same pattern, with relatively fewer cases in lower-income countries. A possible explanation could be underreporting or inadequate medical record keeping in resource-limited settings. However, a more plausible explanation would be that children with familial history of disease are diagnosed and treated early in HICs so that they survive to childbearing age, whereas this may not be the case in LMICs.

Nearly all essential diagnostic and therapeutic modalities were available in most participating treatment centers. Enucleation surgery, which was available in all treatment centers, can save lives, and intravenous chemotherapy, which was available for 98.0% of the patients in this study, can save lives and also result in globe salvage if patients are diagnosed and treated in time.27,28

The results of this study point to an urgent need to improve retinoblastoma detection and access to treatment in LMICs. Several initiatives are addressing this challenge by implementing twinning programs that link centers from higher-resource and lower-resource countries.12,29,30,31,32 However, there is a pressing need for coordinated action on a global level. In a rare yet curable cancer such as retinoblastoma, with approximately 8000 new patients annually worldwide, such an action is feasible to make retinoblastoma a zero-death cancer.33 The World Health Organization Global Initiative for Childhood Cancer aims to raise survival for key childhood cancers, including retinoblastoma, to 60% by the year 2030 by helping health systems in LMICs integrate childhood cancer into their national strategies and improve their capacity to diagnose and deliver curative treatment.34 In this context, accurate retinoblastoma-specific data are essential. The results of this study serve as a report of the current retinoblastoma presentation status, against which future interventions can be measured, and demonstrate the need for a strong global partnership to improve outcomes for patients with retinoblastoma everywhere.

Results of the present study showed that older age at presentation and, independently, national income level were associated with advanced disease, which suggests that other factors besides age may be important in disease progression. It has been suggested that infection by the human papillomavirus, which is more prevalent in LMICs, is associated with the development of nonhereditary retinoblastoma, and it is possible that this could be associated with more aggressive disease behavior.35 Another possible explanation relates to the genetic landscape of retinoblastoma and especially to cases with no RB1 mutation but a high level of amplification of the oncogene MYCN.36 These cases are unilateral, develop at an early age, and show aggressive features. They were found only in 1.4% of unilateral retinoblastoma cases, all from cohorts in HICs,36 but have not been evaluated in patients from LICs. Notably, in the present study, there were substantially more unilateral cases in LICs as compared with other income levels, in keeping with the above-mentioned hypotheses. However, these speculations, warrant further studies.

Limitations

This study has several limitations. First, it included a convenience sample and therefore had an inherent potential bias. Nevertheless, to our knowledge, it is the largest and most geographically comprehensive study in the field of retinoblastoma, and we believe its findings can be generalized. Second, data collection was mostly retrospective, with the exception of treatment centers that were recruited early in 2017. However, the simplicity of the study design and quality assurance process enabled the collection of almost complete data, also from LMICs. Third, the socioeconomic status of individual families was not included as a variable, and the national income level was used as a surrogate, an approach that assumes that all families from the same country are of the same socioeconomic level.

Conclusions

The findings of this cross-sectional global analysis of retinoblastoma at the time of diagnosis revealed important differences in presentation among patients from different countries, depending on their national income level. Patients with retinoblastoma from HICs present with early disease and are, therefore, likely to survive. In contrast, patients from lower-income settings present with late disease, many with extraocular extension and some already with metastasis, and their prognosis is poorer. A familial history of retinoblastoma is relatively uncommon in lower-income countries, likely owing to death related to late-disease presentation before childbearing years. A surprise finding of this study is that more advanced disease at presentation in lower-income countries is not entirely explained by older age. Further research is warranted to investigate what factors other than age play a role in disease progression in low-income settings. Prompt action at national and international levels is warranted to improve health education about retinoblastoma, as well as access to early diagnosis and treatment in retinoblastoma treatment centers in LMICs.

Supplement.

eMethods. Data quality assurance

eTable 1. Sample of the data collection form

eTable 2. Simplified American Joint Committee on Cancer (AJCC) clinical Tumor, Node, Metastasis, Heredity (cTNMH) and International Retinoblastoma Staging System (IRSS)

eTable 3. First sign as noticed by parents and presenting sign at retinoblastoma center

eTable 4. Statistical analysis of clinical variables at presentation by national-income level (Fisher’s exact test)

eTable 5. Analysis of age at presentation by national-income level (Pearson Chi-square test)

eTable 6. Available diagnostic facilities and treatment modalities for the study patients

Click here for additional data file. (1.2MB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eMethods. Data quality assurance

eTable 1. Sample of the data collection form

eTable 2. Simplified American Joint Committee on Cancer (AJCC) clinical Tumor, Node, Metastasis, Heredity (cTNMH) and International Retinoblastoma Staging System (IRSS)

eTable 3. First sign as noticed by parents and presenting sign at retinoblastoma center

eTable 4. Statistical analysis of clinical variables at presentation by national-income level (Fisher’s exact test)

eTable 5. Analysis of age at presentation by national-income level (Pearson Chi-square test)

eTable 6. Available diagnostic facilities and treatment modalities for the study patients

Click here for additional data file. (1.2MB, pdf)

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