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Incidence of Retinoblastoma Has Increased: Results from 40 European Countries

Published:January 25, 2021DOI:https://doi.org/10.1016/j.ophtha.2021.01.024

      Keywords

      Retinoblastoma is the most common intraocular malignancy. Its incidence has been reported to be 1 case in from 15 000 to 18 000 live births, or approximately 12, 6, or 4 cases per 1 million children younger than 5, 10, or 15 years, respectively.
      • Broaddus E.
      • Topham A.
      • Singh A.D.
      Incidence of retinoblastoma in the USA: 1975–2004.
      ,
      • Seregard S.
      • Lundell G.
      • Svedberg H.
      • Kivelä T.
      Incidence of retinoblastoma from 1958 to 1998 in Northern Europe: advantages of birth cohort analysis.
      The aim of this study was to estimate the incidence of retinoblastoma across European countries within a 1-year time frame. Data were collected through an international, multicenter, 1-year cross-sectional analysis that has been described in detail previously.
      • Fabian I.D.
      • Abdallah E.
      • Abdullahi S.U.
      • et al.
      Global retinoblastoma presentation and analysis by national income level.
      Briefly, retinoblastoma treatment centers reported all new cases of retinoblastoma that were diagnosed between January 2017 and December 2017. The final analysis involved only those countries that described their data as being likely complete. The human ethics committees of the London School of Hygiene and Tropical Medicine as well as the ethics committees of all local hospitals approved the study. All research adhered to the tenets of the Declaration of Helsinki. The requirement for informed consent was waived because of the retrospective nature of the study.
      Two methods were used to estimate the incidence rate of retinoblastoma: the live birth method and the age cohort method. Country population estimates and birth rates were retrieved from the World Bank Population Prospects and the United Nations database for 2017. The formula used to calculate the live-birth incidence rate in each country is:
      Incidence (live birth)=No.  of Retinoblastoma Cases in 2017Population in 2017× Crude Birth Rate in 2017


      The formula used to calculate the age cohort incidence rate (per 1 million children younger than 5 years) is:
      Incidence (age cohort)=No. of Retinoblastoma Cases in2017Population Estimate Age<5Years in2017×1Million


      Bootstrap sampling was used to estimate the distribution of each incidence rate. Linear regression analysis was conducted to identify factors that may affect the country-level incidence rate, including the following variables: age at diagnosis, proportion of bilateral cases, proportion of familial cases, proportion of male births, and per capita gross domestic product for the year 2017 (World Bank database). Summary data were calculated for each country and European region (north, south, east, west). An α level of 0.05 was used.
      From the original 40 countries (with 517 retinoblastoma patients), 24 countries were identified as representing likely-complete national-level data, and all 294 patients from these 24 countries were included in the analysis (Table 1). The number of live births for the year 2017 was calculated for each country and region (Table 1). The combined data resulted in a live birth incidence rate of 1 in 13 915 (confidence interval [CI], 12 315–15 150), or 7.2 per 100 000, live births in Europe. The analysis was repeated with the United Nations population data and similar outcomes were seen for each country and overall (1 in 13 844 live births; CI, 12 309–15 083). The highest live birth incidence was seen in northern Europe (1 in 12 907 live births), whereas the lowest incidence rate was seen in southern Europe (1 in 17 177 live births; Fig S1, available at www.aaojournal.org).
      Table 1European Countries Included in the Analysis with the Corresponding Number of New Patients and Calculated Incidence Rates
      European RegionCountryNew Patients Reported in 2017Calculated Births (World Bank)Live Births per 1 New Diagnosis (World Bank)Live Births per 1 New Diagnosis (United Nations)Incidence per 1 Million Children Younger than 5 Yrs (United Nations)Incidence per 1 Million Children Younger than 15 Yrs (United Nations)Incidence per 1 Million Children Younger than 15 Yrs (World Bank)
      EastBulgaria763 6849098908722.410.710.8
      Poland28402 53314 37613 38515.55.05.0
      Armenia342 10514 03513 90214.15.05.0
      Czech Republic8114 42014 30213 90115.04.94.9
      Ukraine34421 41312 39412 56914.74.94.9
      Belarus6102 58117 09718 64810.43.83.8
      Slovakia258 20029 10028 5447.22.42.4
      Georgia2
      Hungary5
      Moldova3
      Romania8
      Russian Federation84
      Subtotal1901 204 93513 69213 49614.65.25.2
      NorthDenmark1061 1096111612035.010.610.5
      Norway956 4646274651129.99.69.7
      Finland750 1257161736224.47.87.8
      Estonia113 83313 83313 66214.94.74.7
      Lithuania228 56714 28314 69913.24.84.8
      United Kingdom51753 07114 76615 10312.74.34.4
      Sweden7115 66416 52316 82312.04.04.0
      Latvia120 78220 78220 9889.93.33.3
      Ireland262 01531 00830 9635.91.91.9
      Subtotal901 161 62812 90713 17016.35.85.8
      SouthPortugal586 52317 30516 12411.93.63.6
      Spain23391 38317 01717 27211.33.43.4
      Slovenia120 25120 25120 1859.53.23.2
      Albania3
      Bosnia and Herzegovina3
      Croatia1
      Greece4
      Italy31
      Kosovo2
      Malta1
      North Macedonia1
      Serbia9
      Subtotal84498 15617 17717 17411.33.93.9
      WestAustria987 9769775973621.27.27.2
      The Netherlands16169 60010 60010 72518.15.75.7
      Switzerland787 05412 43612 46616.05.65.6
      France49762 26315 55614 86712.94.24.0
      Belgium6119 43919 90720 6949.43.13.1
      Andorra1
      Germany65
      Subtotal1531 226 33114 09613 78314.14.84.7
      Overall5174 091 051791313 84414.14.64.6
      — = In countries without complete data, no calculation of incidence was completed.
      Data are grouped by region and completeness (countries with incomplete data are listed in their region, but no calculations were made with their incomplete data).
      The combined age cohort incidence rate was 14.1 per 1 million children younger than 5 years (CI, 12.9–15.9 per 1 million children younger than 5 years) and 4.6 per 1 million children younger than 15 years (CI, 4.1–5.2 children younger than 15 years; Table 1). The age cohort results were used in a linear regression analysis (Table S2, available at www.aaojournal.org). No significant relationship was found between incidence rate and country gross domestic product. The only variable that resulted in a significant association with incidence rate was the proportion of familial cases (P = 0.002), which showed an increasing relationship between the proportion of familial cases and the incidence rate within that country. A similar trend was present for the countries grouped by region (Fig S2, available at www.aaojournal.org).
      The incidence rates calculated in this study—1 in 13 844 live births or 14.1 and 4.6 per 1 million children younger than 5 and 15 years, respectively—are higher than those reported previously. Although some studies have suggested stable incidence rates over many years through the early 2000s,
      • Broaddus E.
      • Topham A.
      • Singh A.D.
      Incidence of retinoblastoma in the USA: 1975–2004.
      ,
      • Seregard S.
      • Lundell G.
      • Svedberg H.
      • Kivelä T.
      Incidence of retinoblastoma from 1958 to 1998 in Northern Europe: advantages of birth cohort analysis.
      ,
      • MacCarthy A.
      • Birch J.M.
      • Draper G.J.
      • et al.
      Retinoblastoma in Great Britain 1963–2002.
      recent national data from Finland document an increase from approximately 1 in 16 700 live births to 1 in 12 500 live births from 1990 to 2014.
      • Nummi K.
      • Kivelä T.T.
      Retinoblastoma in Finland, 1964–2014: incidence and survival.
      The increase in Finland was not evident when familial retinoblastoma was excluded. Our study supports the conclusion that the incidence of retinoblastoma has increased in recent decades even more widely in Europe because of an increasing number of familial patients.
      Improvements in treatments in higher-income countries are leading to less visual impairment,
      • Stacey A.W.
      • Clarke B.
      • Moraitis C.
      • et al.
      The incidence of binocular visual impairment and blindness in children with bilateral retinoblastoma.
      better eye preservation, and better survival. This has led to a reduction in the coefficient of selection, increased fitness, and an increased percentage of familial retinoblastoma in high-income countries.
      • Fabian I.D.
      • Abdallah E.
      • Abdullahi S.U.
      • et al.
      Global retinoblastoma presentation and analysis by national income level.
      As the percentage of familial cases increases, the overall incidence of retinoblastoma should increase. The results of this study document this increase throughout Europe.
      One important finding from these data comes from 2 large countries included in the study whose completeness could not be verified: Italy and Germany. These countries reported high numbers of cases, with the combined incidence for Italy (31 cases) and Germany (65 cases) corresponding to 1 in 12 900 live births. If the data from the 2 largest countries with potentially missing data were included in the study, they would support further the higher than previously reported incidence rate estimate, although their results may be underestimates of their true incidence rates. In this study, Russia was the country with the largest number of patients (n = 84) that was not included in the main analysis, but those data are known to be incomplete because of nonparticipation of some centers outside the capital, Moscow.
      Limitations of this study include its method of data collection and its short duration. The latter limitation introduces bias and variability into the results because the incidence rate of this rare cancer is not constant from one year to the next. However, the number of new cases used for this analysis (294 patients from 24 countries) is robust and larger than the number used for the recent 50-year-long analysis of incidence in Finland (213 patients) and 40-year-long analysis in Sweden (291 patients).
      • Seregard S.
      • Lundell G.
      • Svedberg H.
      • Kivelä T.
      Incidence of retinoblastoma from 1958 to 1998 in Northern Europe: advantages of birth cohort analysis.
      ,
      • Nummi K.
      • Kivelä T.T.
      Retinoblastoma in Finland, 1964–2014: incidence and survival.
      Current data from European countries demonstrate a higher estimate of the incidence of retinoblastoma than what has been reported for previous periods. The incidence of retinoblastoma likely has increased because of improved survival, reproductive capabilities, and confidence of survivors of heritable retinoblastoma. To the best of our knowledge, the increased frequency of carriers of germline RB1 pathogenic variants in Europe illustrates for the first time the selection relaxation effect of therapeutic intervention for a lethal disorder after only a few generations.

      Supplementary Data

      References

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