Retinoblastoma is the most common childhood intraocular cancer, and it accounts for 6.1% of cancer in children younger than 5 years.1 The incidence of retinoblastoma is estimated between 1 in 14,000 and 1 in 34,000 live births, with approximately 8,000 children diagnosed each year worldwide.2 Retinoblastoma is caused by the biallelic loss of function mutation in the retinoblastoma susceptibility gene RB1. RB1 is the first described tumor-suppressor gene and was used to describe the “two-hit hypothesis” model of cancer initiation.3 This genetic mutation deregulates the cell cycle in retinoblasts, causing the cells to undergo uncontrollable proliferation and fail to differentiate into intraretinal photoreceptor and nerve cells. Most patients with retinoblastoma are born with a congenital loss of one RB1 allele and then lose the other copy several years after birth.4
Clinically, although not specific to retinoblastoma, leukocoria is the most common initial sign of retinoblastoma, where the white tumor reflects light and prevents the visualization of the retinal red reflex.4 Children with retinoblastoma may also present with strabismus, deteriorating vision, or red and irritated eye(s). In advanced stages, usually observed in developing countries, eye enlargement is a common finding. Retinoblastoma presents as two clinical ocular forms: bilateral or unilateral. Although bilateral (multifocal) cases are heritable due to germ line mutations of the RB1 gene, unilateral (unifocal) disease is mostly sporadic and non-heritable.5 If detected early, both forms of retinoblastoma have excellent prognoses.6 Thus, early diagnosis and management is critical to the successful treatment of retinoblastoma.
Because the epidemiology and geographic distribution of retinoblastoma are largely unknown in Canada, the precise risk factors are poorly understood. This study aimed to evaluate the incidence rates and geographic distribution of retinoblastoma in Canada between 1992 and 2010.
Patients and Methods
This study was conducted in accordance with the CISS-RDC-668035 and 13-SSH-MCG-3749-S001 protocols approved by the Social Sciences and Humanities Research Council of Canada (SSHRC) and the Québec Inter-University Centre for Social Statistics (QICSS), respectively. In accordance with the institutional policy, this study received an exemption from the McGill University Research Ethics Board review.
We examined the data on retinoblastoma incidence and geographic distribution in Canada between 1992 and 2010 using two distinct population-based cancer registries (Canadian Cancer Registry [CCR] and Le Registre Québécois du Cancer [LRQC]), International Classification of Diseases for Oncology (ICD-O-3) codes, and the same methodology detailed in our previous analyses of melanoma, cutaneous lymphoma, and acute myeloid leukemia incidence and distribution in Canada.7–9 The subtypes of retinoblastoma analyzed and corresponding ICD-O-3 codes are summarized in Table A (available in the online version of this article).8,10
ICD-O-3 Codes Used to Recall Retinoblastoma
The CCR is a database of all Canadian residents from 12 Canadian provinces and territories (excluding Québec) who were diagnosed as having primary tumors between 1992 and 2013. Data for patients in Québec were obtained from the LRQC, which belongs to the Ministère de la Santé et des Services Sociaux. Data from the LRQC database were available between 1992 and 2010. Data on new cases of the previously indicated subtypes of retinoblastoma were obtained from the CCR (2014 version). Because data from the LRQC were not available after 2010, we analyzed data from the CCR and LRQC between 1992 and 2010. The geographical and clinical information provided by the CCR and LRQC were patient sex, laterality of the tumor, year of diagnosis, age at the time of diagnosis, province and city of residence, and the ICD-O-3 code of the tumor. The CCR and LRQC do not collect data on clinical disease stage at the time of diagnosis or on demographic characteristics such as race.
Mandatory Data Rounding
Confidentiality rules apply to the data from the CCR and LRQC prior to publication, such as random rounding of variables. With respect to the random rounding of tabular data, the SSHRC/Statistics Canada requires that each cell count be rounded, independently of other cells, to a lower or higher multiple of 5 using a random rounding scheme. Numbers greater than or equal to 1 and less than 5 cases cannot be released as per the SSHRC regulation to protect patient confidentiality.
Statistical and Mapping Analyses
Crude incidence rates and 95% confidence intervals (95% CIs) were calculated and reported overall, by year of diagnosis, and for specific regions (provinces and cities). CIs were based on exact Poisson distributions. Incidence rates were plotted and linear regression models were used to assess trends over time. Data on population counts nationally, per province, and per city were obtained from the Canadian Census of Population Program from Statistics Canada.
Four hundred forty-five patients were diagnosed as having retinoblastoma in Canada between 1992 and 2010. The characteristics of the reported cases are summarized in Table 1. At the time of diagnosis, the mean age was 2.35 ± 6.85 years, and the male-to-female incidence rate was 1:1.02 (M:F:220:225). The laterality of reported retinoblastoma cases was 81.48% for unilateral cases and 18.52% for bilateral cases. Laterality was reported in 32% of all patients in the studied databases.
Clinical Characteristics of Patients With Retinoblastoma
The overall incidence rate of retinoblastoma for children younger than 5 years old between 1992 and 2010 is listed in Table B (available in the online version of this article). The average annual incidence rate was 11.58 cases per 1 million children younger than 5 years (95% CI: 10.48 to 12.76), and ranged from 7.83 (1997) to 19.48 (2008) cases per 1 million children younger than 5 years. Linear regression analyses of the retinoblastoma incidence rates per 1 million children younger than 5 years old revealed no statistically significant changes in incidence during the study period (coefficient of determination [R2] = 0.08; P = .60) (Figure 1).
Average Annual Incidence Rate of Retinoblastoma in Canada Between 1992 and 2010
Showing incidence rates of retinoblastoma between 1992 and 2010 in Canada, with the line of best fit and linear regression analysis of the incidence rate over time. The slope of the line = 0.08 ± 0.16 and the average annual incidence rate was 11.58 cases per 1 million children younger than 5 years. Coefficient of determination R2 = 0.016; P = .60; CI = confidence interval
The incidence rates of retinoblastoma were also investigated for Canadian cities and provinces (Table 2, Figures 2–3). Only Nova Scotia had significantly higher incidence rates than the national average (Table 2, Figure 2). Conversely, Manitoba had the lowest incidence rate of retinoblastoma in Canada. Incidence rates of retinoblastoma across Canadian cities were comparable to the national average. As expected, the total number of cases was higher in larger cities (including Toronto, Montréal, and Calgary), but the incidence rate in those cities was comparable with the Canadian national average (Table 2, Figure 3).
Average Annual Incidence Rate of Retinoblastoma
Geographic map showing the average annual incidence rate of retinoblastoma across Canadian provinces between 1992 and 2010. Annual incidence rates of retinoblastoma are per 1 million children younger than 5 years.
Geographic maps showing the incidence rate of retinoblastoma across Canadian cities between 1992 and 2010. Annual incidence rates of retinoblastoma are per 1 million children younger than 5 years.
Retinoblastoma is mainly a pediatric cancer. In the United States, 66% and 95% of the reported patients were diagnosed at younger than 2 and 5 years, respectively.11 In the current study, 60% of patients were diagnosed at younger than 2 years and 94% of all patients were diagnosed before 5 years of age. Between 1992 and 2010, there were 445 cases of retinoblastoma and 405 cases occurred in children younger than 5 years. These results correspond to an average annual incidence rate of 11.58 (95% CI: 10.48 to 12.76) cases per 1 million children younger than 5 years. The data are within the range of the rates reported by the United States12 and northern European countries.13 The mean incidence rate of retinoblastoma in the United States between 1973 and 2012 was 12.14 (95% CI: 11.32 to 12.96) cases per 1 million children younger than 5 years.12 The incidence rate of retinoblastoma in the United States has remained stable for the past 30 years. Similarly, our study found a stable incidence of retinoblastoma in children younger than 5 years in Canada. In both the United States and Canada, there was no significant sex predilection, nor was there any significant variation of incidence between sexes.14
Worldwide, the proportion of bilateral cases of retinoblastoma versus unilateral cases was estimated to be 18% to 37% and 63% to 82%, respectively.14 The split between bilateral and unilateral cases was 29% and 71%6 in the United States, 37% and 63% in Sweden and Great Britain, and 18% and 82% in South Africa.15 Although Canadian data are limited by the 32% rate of laterality reporting, we documented that the Canadian proportion of bilateral versus unilateral retinoblastoma cases among those reported was consistent with the international trends stated previously.
The global incidence rate of retinoblastoma is highly variable, with up to 50-fold differences in geographical regions and individual countries.16 The annual incidence rate is 6 to 12 cases per 1 million children younger than 5 years in Europe, the United States, and Australia.12,17 The annual incidence rate was documented in one study18 as 21.8 cases per 1 million children in Mexico, was in the range of 6 to 20 cases per 1 million children in Asia,19 and varied between 6 and 60 cases per 1 million children in Africa.20 Interestingly, there was no significant trend in the age-adjusted incidence rate between races in the United States.14 However, Parkin et al.16 reported that the incidence rate of retinoblastoma in the native populations of Hawaii and Alaska is approximately twice the national average in the United States, which suggests variations in environmental exposures and/or genetic susceptibility for this cancer. Racial predilection for retinoblastoma could not be addressed in the Canadian population due to unavailability of such data in the examined databases.
Risk factors that have been associated with retinoblastoma include advanced parental age,21 use of assisted reproductive technology,22 human papillomavirus infection,23 diet,24 sunlight exposure,25 direct fetal x-ray exposure,23 and parental exposure to hazardous occupational substances.26 Of particular interest, paternal employment as a welder, mechanist, or related metal works have been associated with an increased risk of sporadic retinoblastoma.26
Other risk factors are likely to affect disease pathogenesis. Nova Scotia was the only province with a significantly higher incidence of retinoblastoma (twice the national average). Additionally, Nova Scotia has the highest number of individuals employed in the fishing industry.27 Interestingly, although based on a small sample size, children of Swedish fishermen had a statistically significant increase in the incidence rate of retinoblastoma compared to referent children.28 In addition to possible environmental and genetic factors, the high incidence rate may be attributed to the fact that Nova Scotia had the highest density of ophthalmologists for the analyzed period, which positively correlates with higher reporting and could introduce a detection bias in this case.29 Due to the CCR and LRQC rounding limitations and the small population size for children younger than 5 years, we were not able to identify any statistically significant high incidence of retinoblastoma in cities in Canada.
We also would like to highlight that the CCR is a government-run national registry. Because Canada's health care system is a single tier (payer), which is funded and operated by the provincial governments, the data are collected consistently, where each provincial/territorial cancer registry identifies tumors in its population by combining information from several sources. The CCR performs multiple rigorous processes to ensure comprehensive reporting and accuracy, including an internal record linkage to identify possible duplicate records. Several studies have investigated the detection rates and the accuracy of the diagnostic data in the largest provincial branch of the CCR: the Ontario Cancer Registry. A case ascertainment of close to 100%, a detection rate (detecting and accurately assigning index tumor site) of 81.4% to 96%, and a confirmation rate (correctly assigning tumor site) of 90.9% were shown by these studies,30–32 which confirm a high quality of data and detection rates in the examined registry.
This study had limitations. There are no available data on the ethnicity and clinical stage at the time of diagnosis for patients with retinoblastoma. To further emphasize the laterality, reporting only 32% of cases and the lack of genetic testing results in the CCR/LRQC databases is an important limitation. Another important limitation is our inability to present all of the data due to federal confidentiality regulations. Although mandatory case rounding does not affect trends in the presented results, suppressed data (due to low numbers) in some cities, provinces, or territories limits our ability to present the detailed picture of retinoblastoma burden in Canada.
Analyzing the epidemiology for retinoblastoma in Canada and around the world will help identify its triggers and improve our understanding of the disease. Furthermore, this study provides a foundation on which to monitor Canadian retinoblastoma incidence patterns and can serve to further stimulate etiologic research.
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Clinical Characteristics of Patients With Retinoblastomaa
|Characteristic||No. of Casesb||Cases (%)c||Average Age at Diagnosis (y)d|
| 9,510 Retinoblastoma, NOS||385||86.52||2.43 ± 7.27|
| 9,511 Retinoblastoma, differentiated||30||6.74||1.60 ± 1.89|
| 9,512 Retinoblastoma, undifferentiated||20||4.49||1.91 ± 2.2|
| Retinoblastoma, other subtypes||10||2.25|
| Total||445||100||2.35 ± 6.85|
| Right eye||55||12.36|
| Left eye||55||12.36|
|Age at diagnosis (years)|
| < 1||150||33.71|
| > 5||25||5.62|
Average Annual Incidence Rate of Retinoblastomaa
|Geographic Distribution||No. of Casesb||Population < 5 Yearsc||Incidence Rated||95% CI|
| Nova Scotia||20||43,985||23.93||14.62 to 36.96|
| New Brunswick||10||36,525||14.41||6.91 to 26.50|
| Quebec||110||440,840||13.13||10.79 to 15.83|
| Alberta||55||244,880||11.82||8.91 to 15.39|
| Ontario||150||704,260||11.21||9.49 to 13.15|
| British Columbia||45||219,665||10.78||7.86 to 14.43|
| Saskatchewan||10||68,760||7.65||3.67 to 14.08|
| Manitoba||5||77,185||3.41||1.11 to 7.96|
| Newfoundland and Labrador||< 5|
| Prince Edward Island||< 5|
| Northern territories||< 5|
| Brampton||10||37,380||14.08||6.75 to 25.89|
| Mississauga||10||39,170||13.44||6.44 to 24.71|
| Halifax||5||19,965||13.18||4.28 to 30.76|
| Calgary||15||72,010||10.96||6.14 to 18.08|
| Ottawa||10||49,140||10.71||5.14 to 19.70|
| Vancouver||5||24,770||10.62||3.45 to 24.79|
| Montreal||20||106,425||9.89||6.04 to 15.28|
| Toronto||20||140,510||7.49||4.58 to 11.57|
|Canada (total)||405||1,840,846||11.58||10.48 to 12.76|
ICD-O-3 Codes Used to Recall Retinoblastoma
Average Annual Incidence Rate of Retinoblastoma in Canada Between 1992 and 2010a
|Year||Total Canadian Populationb||Population < 5 Years b||No. of ROP Casesc||Incidence Rated|