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The Incidence of Trilateral Retinoblastoma: A Systematic Review and Meta-Analysis

Open AccessPublished:September 12, 2015DOI:https://doi.org/10.1016/j.ajo.2015.09.009

      Purpose

      To estimate the incidence of trilateral retinoblastoma in patients with retinoblastoma.

      Design

      Systematic review and meta-analysis.

      Methods

      We searched Medline and Embase for scientific literature published between January 1966 and July 2015 that assessed trilateral retinoblastoma incidence. We used a random-effects model for the statistical analyses.

      Results

      We included 23 retinoblastoma cohorts from 26 studies. For patients with bilateral retinoblastoma the unadjusted chance of developing trilateral retinoblastoma across all cohorts was 5.3% (95% confidence interval [CI]: 3.3%–7.7%); the chance of pineal trilateral retinoblastoma was 4.2% (95% CI: 2.6%–6.2%) and the chance of nonpineal trilateral retinoblastoma was 0.8% (95% CI: 0.4%–1.3%). In patients with hereditary retinoblastoma (all bilateral cases, and the unilateral cases with a family history or germline RB1 mutation) we found a trilateral retinoblastoma incidence of 4.1% (95% CI: 1.9%–7.1%) and a pineal trilateral retinoblastoma incidence of 3.7% (95% CI: 1.8%–6.2%). To reduce the risk of overestimation bias we restricted analysis to retinoblastoma cohorts with a minimum size of 100 patients, resulting in adjusted incidences of 3.8% (95% CI: 2.4%–5.4%), 2.9% (95% CI: 1.9%–4.2%), and 0.7% (95% CI: 0.3%–1.2%) for any, pineal, and nonpineal trilateral retinoblastoma, respectively, among patients with bilateral retinoblastoma. Among hereditary retinoblastoma we found an adjusted trilateral retinoblastoma incidence of 3.5% (95% CI: 1.2%–6.7%) and a pineal trilateral retinoblastoma incidence of 3.2% (95% CI: 1.4%–5.6%).

      Conclusion

      The estimated incidence of trilateral retinoblastoma is lower than what is reported in previous literature, especially after exclusion of small cohorts that were subject to overestimation bias in this context.
      Until the age of about 7 years patients with hereditary retinoblastoma are at risk of having an intracranial midline primitive neuroectodermal tumor diagnosed, and among patients diagnosed since 1995 more than 95% have developed trilateral retinoblastoma before the age of 5 years.
      • Jakobiec F.A.
      • Tso M.O.
      • Zimmerman L.E.
      • Danis P.
      Retinoblastoma and intracranial malignancy.
      • Kivelä T.
      Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma.
      • De Jong M.C.
      • Kors W.A.
      • de Graaf P.
      • Castelijns J.A.
      • Kivelä T.
      • Moll A.C.
      Trilateral retinoblastoma: a systematic review and meta-analysis.
      In histopathologic analysis these tumors look similar to corresponding retinal tumors. When unilateral or bilateral retinoblastoma and an intracranial midline primitive neuroectodermal tumor both occur in a patient, this is referred to as trilateral retinoblastoma, which can be found in the pineal gland (pineal trilateral retinoblastoma) in about three-quarters of cases; in the remaining patients it develops in other midline brain regions (nonpineal trilateral retinoblastoma), usually the suprasellar and parasellar region, although other brain regions have been reported also.
      • De Jong M.C.
      • Kors W.A.
      • de Graaf P.
      • Castelijns J.A.
      • Kivelä T.
      • Moll A.C.
      Trilateral retinoblastoma: a systematic review and meta-analysis.
      • Katayama Y.
      • Tsubokawa T.
      • Yamamoto T.
      • Nemoto N.
      Ectopic retinoblastoma within the 3rd ventricle: case report.
      • Dudgeon J.
      • Lee W.R.
      The trilateral retinoblastoma syndrome.
      In a recent meta-analysis we showed that survival has improved considerably in the last 2 decades, from hardly any to almost half of all patients.
      • De Jong M.C.
      • Kors W.A.
      • de Graaf P.
      • Castelijns J.A.
      • Kivelä T.
      • Moll A.C.
      Trilateral retinoblastoma: a systematic review and meta-analysis.
      Favorable survival after pineal trilateral retinoblastoma depended strongly on early detection and small tumor size. The improved survival after trilateral retinoblastoma was highly associated with the use of (improved) chemotherapy regimens, especially high-dose chemotherapy with stem cell rescue.
      • De Jong M.C.
      • Kors W.A.
      • de Graaf P.
      • Castelijns J.A.
      • Kivelä T.
      • Moll A.C.
      Trilateral retinoblastoma: a systematic review and meta-analysis.
      Previous radiotherapy for retinoblastoma, especially before the age of 12 months, has been associated with a potentially higher incidence of pineal trilateral retinoblastoma in patients with hereditary retinoblastoma, even though the pineal gland is usually not (directly) within the field of radiation.
      • Moll A.C.
      • Imhof S.M.
      • Schouten-Van Meeteren A.Y.
      • Kuik D.J.
      • Hofman P.
      • Boers M.
      Second primary tumors in hereditary retinoblastoma: a register-based study, 1945–1997.
      Whether previous systemic chemotherapy is protective of developing trilateral retinoblastoma is still being debated.
      • Moll A.C.
      • Imhof S.M.
      • Schouten-van Meeteren A.Y.N.
      • Boers M.
      • van Leeuwen F.
      • Hofman P.
      Chemoreduction for retinoblastoma.
      • Ramasubramanian A.
      • Kytasty C.
      • Meadows A.T.
      • Shields J.A.
      • Leahey A.
      • Shields C.L.
      Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era.
      • Marees T.
      • Moll A.C.
      • Imhof S.M.
      • de Boer M.R.
      • Ringens P.J.
      • van Leeuwen F.E.
      Re: more about second cancers after retinoblastoma.
      • Chantada G.L.
      • Fandiño A.C.
      • Schvartzman E.
      • Raslawski E.
      • Schaiquevich P.
      • Manzitti J.
      Impact of chemoreduction for conservative therapy for retinoblastoma in Argentina.
      There have been numerous reports on trilateral retinoblastoma incidence, but these studies are quite heterogeneous. Some are referral-based, others population-based. The only previously published study summarizing incidence data across studies reported an incidence of 5%–15% among patients with bilateral retinoblastoma.
      • Kivelä T.
      Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma.
      The objective of this study is to provide an overview of, to critically analyze, and to provide pooled summary estimates of published incidence data for pineal and nonpineal trilateral retinoblastoma.

      Methods

      We performed this systematic review and meta-analysis according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement.
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.

       Search Strategy

      We searched Medline (PubMed) and Embase for English, Dutch, and German literature published from January 1, 1966 through July 15, 2015, evaluating trilateral retinoblastoma cases. We also considered alternatively found studies for inclusion (eg, through checking references in included studies). The search was similar to the search we used in our systematic review and meta-analysis on survival of patients with trilateral retinoblastoma.
      • De Jong M.C.
      • Kors W.A.
      • de Graaf P.
      • Castelijns J.A.
      • Kivelä T.
      • Moll A.C.
      Trilateral retinoblastoma: a systematic review and meta-analysis.
      To ensure a sensitive search, we included only keywords corresponding to the target condition (including retinoblastoma, pineoblastoma, pineal, suprasellar, parasellar, sellar, ectopic, and brain), without any delimiters. For the detailed search see Supplemental Table 1 (available at AJO.com).

       Study Selection and Data Extraction

      Two authors (M.C.J. and A.C.M.) independently reviewed article titles and abstracts for eligibility. Discrepancies were resolved by consensus. Subsequently the same 2 authors independently reviewed eligible full-text articles for inclusion in the systematic review and meta-analysis. Again, discrepancies were solved by consensus.
      We included studies in the systematic review and meta-analysis if (1) the study mentioned the number of patients with trilateral retinoblastoma (can also be 0, as long as authors mentioned evaluating for trilateral retinoblastoma cases), if (2) articles reported details and size of the retinoblastoma cohort in which patients with trilateral retinoblastoma were seen (eg, number of patients with trilateral retinoblastoma diagnosed in a cohort of patients with retinoblastoma during a certain period), and if (3) the full-text article could be obtained. We excluded studies from the systematic review if (1) the article was a review or meta-analysis, and if (2) studies included overlapping incidence data. Two authors (M.C.J. and W.A.K.) independently extracted incidence data. Discrepancies were resolved by consensus. We have defined hereditary retinoblastoma as patients with bilateral retinoblastoma, known familial retinoblastoma, or a detected germline mutation in RB1.

       Data Synthesis and Statistical Analysis

      Ideally, we would present the cumulative incidence of trilateral retinoblastoma until a certain age (eg, up to 5 years) in comparable retinoblastoma cohorts; however, most studies only provided the total number of patients with retinoblastoma and the number of trilateral retinoblastoma cases they found in their cohort. Therefore we are restricted to the calculation of a percentage of cases that developed trilateral retinoblastoma divided by total retinoblastoma cohort from a certain time period. This method unfortunately does not take into account the effect of patients lost to follow-up (ie, assuming that of all patients with retinoblastoma it is unequivocally known whether they developed trilateral retinoblastoma or not).
      In addition to performing unadjusted analysis, we calculated adjusted estimates by including cohorts of at least 100 patients with retinoblastoma, to prevent overestimation bias. Most small cohorts published specifically after encountering at least 1 trilateral retinoblastoma and thus led to a report irrespective of how many patients without trilateral retinoblastoma had been seen (ie, an arbitrary cohort of patients with retinoblastoma with a certain start and end date will have been constructed around the patient(s) with trilateral retinoblastoma that were encountered). The limit of 100 patients was based on visual evaluation of a plot of the incidence of trilateral retinoblastoma against the total sample size across studies (Figure 1). Typically, an unselected patient population contains 40% of bilateral retinoblastoma, and thus we considered also a cohort of at least 40 bilateral retinoblastomas to be large enough to guard for overestimation bias.
      Figure thumbnail gr1
      Figure 1Trilateral retinoblastoma incidence vs the size of the cohorts of patients with unilateral or bilateral retinoblastoma. The estimated curve in this figure is an S-curve with a fit of R2 =0.44, P = .0027.
      To assess the extent of this bias we compared data from developed vs developing countries, as one would expect follow-up to be more complete in developed countries (ie, higher chance to find a trilateral retinoblastoma). This might lead to an underestimation of trilateral retinoblastoma incidence in the developing countries. Pooling data from different retinoblastoma cohorts also assumes comparability of these cohorts.
      To evaluate changes in trilateral retinoblastoma incidence over time we used a cutoff at the year 1995. We chose this cutoff because around (or maybe even before) 1995 treatment of retinoblastoma started to shift from radiotherapy to chemotherapy.
      • Murphree A.L.
      • Villablanca J.G.
      • Deegan W.F.
      • et al.
      Chemotherapy plus local treatment in the management of intraocular retinoblastoma.
      We used a random-effects model to calculate summary estimates of trilateral retinoblastoma incidence.
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      • Barendregt J.J.
      • Doi S.A.
      • Lee Y.Y.
      • Norman R.E.
      • Vos T.
      Meta-analysis of prevalence.
      A random-effects model is used for meta-analyses to account for heterogeneity between studies. For each analysis we calculated I2 to evaluate heterogeneity among included studies; I2 ranges from 0 to 100% with increasing heterogeneity.
      • Higgins J.P.T.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      For the random-effects analyses we used MetaXL (version 2.1; EpiGear, Wilston, Australia) and SAS (Proc MIXED, version 9.3; SAS, Cary, North Carolina, USA). The forest plots were created with Illustrator CS6 (Adobe, San Jose, California, USA).

       Risk of Bias and Study Quality Assessment

      Two authors (M.C.J. and T.K.) assessed the risk of bias with a modified checklist that was developed for prevalence studies by Hoy and associates.
      • Hoy D.
      • Brooks P.
      • Woolf A.
      • et al.
      Assessing risk of bias in prevalence studies: modification of an existing tool and evidence of interrater agreement.
      With the checklist 6 items that could lead to bias were assessed (Supplemental Table 2, available at AJO.com).
      • Marees T.
      • Moll A.C.
      • Imhof S.M.
      • de Boer M.R.
      • Ringens P.J.
      • van Leeuwen F.E.
      Risk of second malignancies in survivors of retinoblastoma: more than 40 years of follow-up.
      • Marees T.
      • van Leeuwen F.E.
      • de Boer M.R.
      • Imhof S.M.
      • Ringens P.J.
      • Moll A.C.
      Cancer mortality in long-term survivors of retinoblastoma.

      Results

      We identified 1865 unique studies from database searches. We excluded 1734 articles based on title and abstract (Figure 2). We excluded 105 studies based on the full text; reasons for exclusion are shown in Figure 2. Twenty-six studies (3 pairs of studies had overlapping cohorts but provided different data of interest and were therefore included; see Table 1) met the inclusion criteria of this systematic review. Twenty-one studies (20 cohorts) were included in the meta-analysis. Tables 2 and 3 show the incidence data as reported in each included study.
      Figure thumbnail gr2
      Figure 2Flow chart of the total number of articles found with PubMed and Embase and subsequent inclusion and exclusion of articles, leading to the number of included articles and retinoblastoma cohorts that contained information on trilateral retinoblastoma incidence.
      Table 1Basic Information About the Retinoblastoma Cohorts of All Included Studies That Presented Trilateral Retinoblastoma Incidence Data
      StudyInclusion PeriodCountrySource of the DataType of Patients With RetinoblastomaAge at Retinoblastoma Diagnosis (Months)Patient Follow-up From Retinoblastoma Diagnosis (Months)Percentage of Cohort With Unilateral RetinoblastomaPercentage of Cohort With Bilateral RetinoblastomaPercentage of Cohort With Familial RetinoblastomaStudy Cohort (Partly) Overlaps With
      Amoaku et al
      • Amoaku W.M.
      • Willshaw H.E.
      • Parkes S.E.
      • Shah K.J.
      • Mann J.R.
      Trilateral retinoblastoma. A report of five patients.
      1960–1994United KingdomPopulation registryAnyMean 6, range 0.75–1764%36%38
      As percentage of the patients with bilateral retinoblastoma.
      Antoneli et al
      • Antoneli C.B.G.
      • Ribeiro K.B.
      • Sakamoto L.H.
      • Chojniak M.M.
      • Novaes P.E.R.S.
      • Arias V.E.A.
      Trilateral retinoblastoma.
      1986–2003Brasil1 centerAny60%40%
      Azar et al
      • Azar D.
      • Donaldson C.
      • Dalla-Pozza L.
      Questioning the need for routine bone marrow aspiration and lumbar puncture in patients with retinoblastoma.
      1975–2001Australia2 centersAnyMean 17.9 (bilateral 22.6, unilateral 3.5)60%40%11
      Bartuma et al
      • Bartuma K.
      • Pal N.
      • Kosek S.
      • Holm S.
      • All-Ericsson C.A.
      10-year experience of outcome in chemotherapy-treated hereditary retinoblastoma.
      2001–2011Sweden1 centerHereditaryMean 8, range 0–39Mean 60, range 13–1448%92%38
      Blach et al
      • Blach L.E.
      • McCormick B.
      • Abramson D.H.
      • Ellsworth R.M.
      Trilateral retinoblastoma–incidence and outcome: a decade of experience.
      1979–1990USA1 centerIrradiatedMedian 7, range <1–60Median 68, range 4–15317%83%27
      Chantada et al
      • Chantada G.L.
      • Fandiño A.C.
      • Schvartzman E.
      • Raslawski E.
      • Schaiquevich P.
      • Manzitti J.
      Impact of chemoreduction for conservative therapy for retinoblastoma in Argentina.
      1988–2012Argentina1 centerBilateralMean 13.9, range 0–114Median 115, range 31–290100%14
      As percentage of the patients with bilateral retinoblastoma.
      Moreno et al
      • Moreno F.
      • Sinaki B.
      • Fandiño A.
      • Dussel V.
      • Orellana L.
      • Chantada G.
      A population-based study of retinoblastoma incidence and survival in Argentine children.
      De Ioris et al
      • De Ioris M.A.
      • Valente P.
      • Randisi F.
      • et al.
      Baseline central nervous system magnetic resonance imaging in early detection of trilateral retinoblastoma: pitfalls in the diagnosis of pineal gland lesions.
      1999–2009Italy1 centerAnyMedian 10, range 0.5–7358%42%14
      De Potter et al
      • De Potter P.
      • Shields C.L.
      • Shields J.A.
      Clinical variations of trilateral retinoblastoma: a report of 13 cases.
      1972–1992United Kingdom1 centerAny54%46%14
      Duncan et al
      • Duncan J.L.
      • Scott I.U.
      • Murray T.G.
      • Gombos D.S.
      • van Quill K.
      • O'Brien J.M.
      Routine neuroimaging in retinoblastoma for the detection of intracranial tumors.
      1990–1998USA2 centersAnyMean 44.8, range 0–139≥63%≤37%
      Helveston et al
      • Helveston E.M.
      • Knuth K.R.
      • Ellis F.D.
      Retinoblastoma.
      1967–1987USA1 centerAnyUnilateral 23, bilateral 10
      Age at treatment; unknown if these are means or medians or some other measure.
      59%41%
      Imhof et al
      • Imhof S.M.
      • Moll A.C.
      • Hofman P.
      • Mourits M.P.
      • Schipper J.
      • Tan K.E.
      Second primary tumours in hereditary- and nonhereditary retinoblastoma patients treated with megavoltage external beam irradiation.
      1971–1993Netherlands1 centerIrradiatedMean 5, range 1–216Mean 148, range 48–276Moll et al
      • Moll A.C.
      • Imhof S.M.
      • Schouten-Van Meeteren A.Y.
      • Kuik D.J.
      • Hofman P.
      • Boers M.
      Second primary tumors in hereditary retinoblastoma: a register-based study, 1945–1997.
      Jubran et al
      • Jubran R.F.
      • Erdreich-Epstein A.
      • Butturini A.
      • Murphree A.L.
      • Villablanca J.G.
      Approaches to treatment for extraocular retinoblastoma: Children's Hospital Los Angeles experience.
      1991–1999USA1 centerAny
      Jurkiewicz et al
      • Jurkiewicz E.
      • Pakuła-Kościesza I.
      • Rutynowska O.
      • Nowak K.
      Trilateral retinoblastoma: an institutional experience and review of the literature.
      1996–2008Poland1 centerAnyUnilateral median 22, bilateral median 12
      Kingston et al
      • Kingston J.E.
      • Plowman P.N.
      • Hungerford J.L.
      Ectopic intracranial retinoblastoma in childhood.
      1954–1983United Kingdom2 centersAny31%69%
      Klufas et al
      • Klufas M.A.
      • Gobin Y.P.
      • Marr B.
      • Brodie S.E.
      • Dunkel I.J.
      • Abramson D.H.
      Intra-arterial chemotherapy as a treatment for intraocular retinoblastoma: alternatives to direct ophthalmic artery catheterization.
      2006–2010USA1 centerTreated with intraarterial chemotherapyMedian 17.5, range 8–36
      Lim et al
      • Lim Y.S.
      • Juraida E.
      • Alagaratnam J.
      • Menon B.S.
      Trilateral retinoblastoma.
      2001–2009Malaysia1 centerAny
      Lim et al
      • Lim F.P.M.
      • Soh S.Y.
      • Iyer J.V.
      • Tan A.M.
      • Swati H.
      • Quah B.L.
      Clinical profile, management, and outcome of retinoblastoma in Singapore.
      1997–2010Singapore1 centerAny25.7, SD 19.9 (unilateral mean: 30.2, SD 21.4, bilateral mean: 15.4, SD 9.6)Median 36, range 0–15669%31%
      Lueder et al
      • Lueder G.T.
      • Judisch F.
      • O'Gorman T.W.
      Second nonocular tumors in survivors of heritable retinoblastoma.
      1924–1985USA1 centerAny67%33%14Lueder et al
      • Lueder G.T.
      • Judisch G.F.
      • Wen B.C.
      Heritable retinoblastoma and pinealoma.
      Lueder et al.
      • Lueder G.T.
      • Judisch G.F.
      • Wen B.C.
      Heritable retinoblastoma and pinealoma.
      1924–1989USA1 centerAny14Lueder et al
      • Lueder G.T.
      • Judisch F.
      • O'Gorman T.W.
      Second nonocular tumors in survivors of heritable retinoblastoma.
      Moll et al
      • Moll A.C.
      • Imhof S.M.
      • Schouten-Van Meeteren A.Y.
      • Kuik D.J.
      • Hofman P.
      • Boers M.
      Second primary tumors in hereditary retinoblastoma: a register-based study, 1945–1997.
      1970–1997NetherlandsPopulation registryHereditaryImhof et al
      • Imhof S.M.
      • Moll A.C.
      • Hofman P.
      • Mourits M.P.
      • Schipper J.
      • Tan K.E.
      Second primary tumours in hereditary- and nonhereditary retinoblastoma patients treated with megavoltage external beam irradiation.
      Moreno et al
      • Moreno F.
      • Sinaki B.
      • Fandiño A.
      • Dussel V.
      • Orellana L.
      • Chantada G.
      A population-based study of retinoblastoma incidence and survival in Argentine children.
      2000–2009ArgentinaPopulation registryAnyUnilateral median 26 (IQR 13–42), bilateral median 10 (IQR 5–19)68%32%Chantada et al
      • Chantada G.L.
      • Fandiño A.C.
      • Schvartzman E.
      • Raslawski E.
      • Schaiquevich P.
      • Manzitti J.
      Impact of chemoreduction for conservative therapy for retinoblastoma in Argentina.
      Popovic et al
      • Popovic M.B.
      • Balmer A.
      • Maeder P.
      • Braganca T.
      • Munier F.L.
      • Beck Popovic M.
      Benign pineal cysts in children with bilateral retinoblastoma: a new variant of trilateral retinoblastoma?.
      1990–2001Switzerland1 centerAny49%51%
      Provenzale et al
      • Provenzale J.M.
      • Gururangan S.
      • Klintworth G.
      Trilateral retinoblastoma: clinical and radiologic progression.
      1985–2002USA1 centerAny52%48%
      Ramasubramanian et al
      • Ramasubramanian A.
      • Kytasty C.
      • Meadows A.T.
      • Shields J.A.
      • Leahey A.
      • Shields C.L.
      Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era.
      • Ramasubramanian A.
      • Meadows A.T.
      • Shields J.A.
      • Leahey A.
      • Shields C.L.
      Reply to: incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era.
      2000–2012USA1 centerAnyMean 21, median 13, range 0–9153%47%11
      Scott et al
      • Scott M.H.
      • Richard J.M.
      Retinoblastoma in the state of Oklahoma: a clinicopathologic review.
      1970–1990USA1 centerAnyMean 15.8 (nonhereditary mean 20.5, hereditary mean 11.7)52%48%
      Shields et al
      • Shields C.L.
      • Meadows A.T.
      • Shields J.A.
      • Carvalho C.
      • Smith A.F.
      Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma).
      1995–1999USA1 centerAnyMean 14, median 8, range 1–87Mean 33, range 0–6748%52%18
      IQR = interquartile range; SD = standard deviation.
      a As percentage of the patients with bilateral retinoblastoma.
      b Age at treatment; unknown if these are means or medians or some other measure.
      Table 2Incidence of Trilateral Retinoblastoma Among Unilateral and Bilateral Retinoblastoma, Bilateral Retinoblastoma, and Hereditary Retinoblastoma for Studies Included in the Meta-analysis
      StudyInclusion PeriodUnilateral and Bilateral RetinoblastomaBilateral RetinoblastomaHereditary Retinoblastoma
      PinealNonpinealPinealNonpinealPinealNonpineal
      Amoaku et al
      • Amoaku W.M.
      • Willshaw H.E.
      • Parkes S.E.
      • Shah K.J.
      • Mann J.R.
      Trilateral retinoblastoma. A report of five patients.
      1960–19942.7% (4/146)0.7% (1/146)7.7% (4/52)1.9% (1/52)
      Antoneli et al
      • Antoneli C.B.G.
      • Ribeiro K.B.
      • Sakamoto L.H.
      • Chojniak M.M.
      • Novaes P.E.R.S.
      • Arias V.E.A.
      Trilateral retinoblastoma.
      1986–20030.6% (3/470)0.2% (1/470)1.1% (2/186)0.5% (1/186)
      Azar et al
      • Azar D.
      • Donaldson C.
      • Dalla-Pozza L.
      Questioning the need for routine bone marrow aspiration and lumbar puncture in patients with retinoblastoma.
      1975–20011.6% (2/123)0.0% (0/123)4.1% (2/49)0.0% (0/49)
      De Ioris et al
      • De Ioris M.A.
      • Valente P.
      • Randisi F.
      • et al.
      Baseline central nervous system magnetic resonance imaging in early detection of trilateral retinoblastoma: pitfalls in the diagnosis of pineal gland lesions.
      1999–20122.8% (3/107)0.0% (0/107)6.7% (3/49)0.0% (0/49)
      De Potter et al
      • De Potter P.
      • Shields C.L.
      • Shields J.A.
      Clinical variations of trilateral retinoblastoma: a report of 13 cases.
      1972–19922.0% (9/440)0.7% (3/440)4.0% (8/202)1.5% (3/202)
      Duncan et al
      • Duncan J.L.
      • Scott I.U.
      • Murray T.G.
      • Gombos D.S.
      • van Quill K.
      • O'Brien J.M.
      Routine neuroimaging in retinoblastoma for the detection of intracranial tumors.
      1990–19980.9% (2/226)0.0% (0/226)2.4% (2/85)
      Duncan et al33 reported that 83 had hereditary retinoblastoma, excluding the 2 pineal trilateral retinoblastoma cases that can be classified as having hereditary retinoblastoma on the basis of developing a midline primitive neuroectodermal tumor (they also presented a case with an “orbital midline primitive neuroectodermal tumor,” but we are not convinced this is trilateral retinoblastoma).
      0.0% (0/85)
      Duncan et al33 reported that 83 had hereditary retinoblastoma, excluding the 2 pineal trilateral retinoblastoma cases that can be classified as having hereditary retinoblastoma on the basis of developing a midline primitive neuroectodermal tumor (they also presented a case with an “orbital midline primitive neuroectodermal tumor,” but we are not convinced this is trilateral retinoblastoma).
      Helveston et al
      • Helveston E.M.
      • Knuth K.R.
      • Ellis F.D.
      Retinoblastoma.
      1967–19871.4% (1/74)0.0% (0/74)3.3% (1/30)0.0% (0/30)
      Jubran et al
      • Jubran R.F.
      • Erdreich-Epstein A.
      • Butturini A.
      • Murphree A.L.
      • Villablanca J.G.
      Approaches to treatment for extraocular retinoblastoma: Children's Hospital Los Angeles experience.
      1991–19991.4% (3/207)0.0% (0/207)
      Jurkiewicz et al
      • Jurkiewicz E.
      • Pakuła-Kościesza I.
      • Rutynowska O.
      • Nowak K.
      Trilateral retinoblastoma: an institutional experience and review of the literature.
      1996–20080.5% (1/202)1.0% (2/202)
      Kingston et al
      • Kingston J.E.
      • Plowman P.N.
      • Hungerford J.L.
      Ectopic intracranial retinoblastoma in childhood.
      1954–19831.3% (8/630)0.5% (3/630)1.9% (8/432)0.5% (2/432)
      Lim et al
      • Lim Y.S.
      • Juraida E.
      • Alagaratnam J.
      • Menon B.S.
      Trilateral retinoblastoma.
      2001–20091.4% (2/141)0.0% (0/141)
      Lim et al
      • Lim F.P.M.
      • Soh S.Y.
      • Iyer J.V.
      • Tan A.M.
      • Swati H.
      • Quah B.L.
      Clinical profile, management, and outcome of retinoblastoma in Singapore.
      1997–20103.9% (2/51)0.0% (0/51)12.5% (2/16)0.0% (0/16)
      Lueder et al
      • Lueder G.T.
      • Judisch F.
      • O'Gorman T.W.
      Second nonocular tumors in survivors of heritable retinoblastoma.
      1924–19852.3% (3/132)0.0% (0/132)6.8% (3/44)0.0% (0/44)6.0% (3/50)0.0% (0/50)
      Lueder et al
      • Lueder G.T.
      • Judisch G.F.
      • Wen B.C.
      Heritable retinoblastoma and pinealoma.
      1924–19892.7% (4/143)7.1% (4/56)
      Moll et al
      • Moll A.C.
      • Imhof S.M.
      • Schouten-Van Meeteren A.Y.
      • Kuik D.J.
      • Hofman P.
      • Boers M.
      Second primary tumors in hereditary retinoblastoma: a register-based study, 1945–1997.
      1970–19975.8% (7/121)0.0% (0/121)
      Moreno et al
      • Moreno F.
      • Sinaki B.
      • Fandiño A.
      • Dussel V.
      • Orellana L.
      • Chantada G.
      A population-based study of retinoblastoma incidence and survival in Argentine children.
      2000–20090.7% (3/438)0.0% (0/438)2.2% (3/139)0.0% (0/139)
      Popovic et al
      • Popovic M.B.
      • Balmer A.
      • Maeder P.
      • Braganca T.
      • Munier F.L.
      • Beck Popovic M.
      Benign pineal cysts in children with bilateral retinoblastoma: a new variant of trilateral retinoblastoma?.
      1990–20011.8% (4/221)0.5% (1/221)3.7% (4/108)0.9% (1/108)
      Provenzale et al
      • Provenzale J.M.
      • Gururangan S.
      • Klintworth G.
      Trilateral retinoblastoma: clinical and radiologic progression.
      1985–200211.1% (7/63)1.6% (1/63)23.3% (7/30)3.3% (1/30)
      Ramasubramanian et al
      • Ramasubramanian A.
      • Kytasty C.
      • Meadows A.T.
      • Shields J.A.
      • Leahey A.
      • Shields C.L.
      Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era.
      • Ramasubramanian A.
      • Meadows A.T.
      • Shields J.A.
      • Leahey A.
      • Shields C.L.
      Reply to: incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era.
      2000–20121.0% (4/408)1.6% (3/193)1.9% (4/215)
      Scott et al
      • Scott M.H.
      • Richard J.M.
      Retinoblastoma in the state of Oklahoma: a clinicopathologic review.
      1970–19905.4% (3/56)0.0% (0/56)11.1% (3/27)0.0% (0/27)10.0% (3/30)0.0% (0/30)
      Shields et al
      • Shields C.L.
      • Meadows A.T.
      • Shields J.A.
      • Carvalho C.
      • Smith A.F.
      Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma).
      1995–19990.5% (1/214)0.0% (0/214)0.9% (1/112)0.0% (0/112)0.9% (1/117)0.0% (0/117)
      The number of trilateral retinoblastoma patients divided by the size of the retinoblastoma cohort in parentheses.
      a Duncan et al
      • Duncan J.L.
      • Scott I.U.
      • Murray T.G.
      • Gombos D.S.
      • van Quill K.
      • O'Brien J.M.
      Routine neuroimaging in retinoblastoma for the detection of intracranial tumors.
      reported that 83 had hereditary retinoblastoma, excluding the 2 pineal trilateral retinoblastoma cases that can be classified as having hereditary retinoblastoma on the basis of developing a midline primitive neuroectodermal tumor (they also presented a case with an “orbital midline primitive neuroectodermal tumor,” but we are not convinced this is trilateral retinoblastoma).
      Table 3The Incidence of Trilateral Retinoblastoma Among Unilateral and Bilateral Retinoblastoma, Bilateral Retinoblastoma, and Hereditary Retinoblastoma for Studies That Assessed the Effect of Previous Chemotherapy or Radiotherapy on the Development of Trilateral Retinoblastoma
      StudyInclusion PeriodTreatment for RetinoblastomaUnilateral and Bilateral RetinoblastomaBilateral RetinoblastomaHereditary Retinoblastoma
      PinealNonpinealPinealNonpinealPinealNonpineal
      Bartuma et al
      • Bartuma K.
      • Pal N.
      • Kosek S.
      • Holm S.
      • All-Ericsson C.A.
      10-year experience of outcome in chemotherapy-treated hereditary retinoblastoma.
      2001–2011Systemic chemotherapy0.0% (0/24)
      Twenty-four patients received a full course of systemic chemotherapy, 1 was previously treated elsewhere, and 2 did not receive (a full course of) chemotherapy; 1 of these latter 2 patients did develop trilateral retinoblastoma (location unspecified).
      0.0% (0/24)
      Twenty-four patients received a full course of systemic chemotherapy, 1 was previously treated elsewhere, and 2 did not receive (a full course of) chemotherapy; 1 of these latter 2 patients did develop trilateral retinoblastoma (location unspecified).
      Chantada et al
      • Chantada G.L.
      • Fandiño A.C.
      • Schvartzman E.
      • Raslawski E.
      • Schaiquevich P.
      • Manzitti J.
      Impact of chemoreduction for conservative therapy for retinoblastoma in Argentina.
      1988–2009Systemic chemotherapy1.9% (3/159)0.0% (0/159)
      No systemic chemotherapy0.0% (0/38)0.0% (0/38)
      Klufas et al
      • Klufas M.A.
      • Gobin Y.P.
      • Marr B.
      • Brodie S.E.
      • Dunkel I.J.
      • Abramson D.H.
      Intra-arterial chemotherapy as a treatment for intraocular retinoblastoma: alternatives to direct ophthalmic artery catheterization.
      2006–2010Intraarterial chemotherapy1.1% (1/89)0.0% (0/89)1.4% (1/70)0.0% (0/70)
      Ramasubramania et al
      • Ramasubramanian A.
      • Kytasty C.
      • Meadows A.T.
      • Shields J.A.
      • Leahey A.
      • Shields C.L.
      Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era.
      • Ramasubramanian A.
      • Meadows A.T.
      • Shields J.A.
      • Leahey A.
      • Shields C.L.
      Reply to: incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era.
      2000–2012Systemic chemotherapy0.4% (1/252)0.6% (1/180)
      No systemic chemotherapy1.9% (3/156)8.6% (3/35)
      Shields et al
      • Shields C.L.
      • Meadows A.T.
      • Shields J.A.
      • Carvalho C.
      • Smith A.F.
      Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma).
      1995–1999Systemic chemotherapy0.0% (0/142)0.0% (0/142)0.0% (0/95)0.0% (0/95)0.0% (0/99)0.0% (0/99)
      No systemic chemotherapy1.4% (1/72)0.0% (0/72)5.9% (1/17)0.0% (0/17)5.6% (1/18)0.0% (0/18)
      Blach et al
      • Blach L.E.
      • McCormick B.
      • Abramson D.H.
      • Ellsworth R.M.
      Trilateral retinoblastoma–incidence and outcome: a decade of experience.
      1979–1990Radiotherapy4.3% (5/117)0.9% (1/117)5.2% (5/97)1.0% (1/97)
      Imhof et al
      • Imhof S.M.
      • Moll A.C.
      • Hofman P.
      • Mourits M.P.
      • Schipper J.
      • Tan K.E.
      Second primary tumours in hereditary- and nonhereditary retinoblastoma patients treated with megavoltage external beam irradiation.
      1971–1993Radiotherapy4.7% (5/106)0.0% (0/106)5.7% (5/87)0.0% (0/87)
      Ramasubramanian et al
      • Ramasubramanian A.
      • Kytasty C.
      • Meadows A.T.
      • Shields J.A.
      • Leahey A.
      • Shields C.L.
      Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era.
      • Ramasubramanian A.
      • Meadows A.T.
      • Shields J.A.
      • Leahey A.
      • Shields C.L.
      Reply to: incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era.
      2000–2012Radiotherapy2.8% (1/87)
      No radiotherapy1.7% (3/179)
      The number of trilateral retinoblastoma patients divided by the size of the retinoblastoma cohort in parentheses.
      a Twenty-four patients received a full course of systemic chemotherapy, 1 was previously treated elsewhere, and 2 did not receive (a full course of) chemotherapy; 1 of these latter 2 patients did develop trilateral retinoblastoma (location unspecified).

       Unadjusted Estimates

      Twenty-six studies reported trilateral retinoblastoma incidence in 23 unique cohorts of patients with retinoblastoma, and in 15 studies (15 cohorts) bilateral could be distinguished from unilateral retinoblastoma (Table 2). Seven studies (6 cohorts) presented the trilateral retinoblastoma incidence in hereditary retinoblastoma, 3 studies (cohorts) reported trilateral retinoblastoma incidence after external beam irradiation for retinoblastoma, and 5 studies (cohorts) compared the incidence in patients with retinoblastoma with and without previous chemotherapy. Forest plots of the included studies (sorted by the midpoint of the study period) and the summary estimates are shown in Figure 3.
      Figure thumbnail gr3
      Figure 3Forest plots of trilateral retinoblastoma incidence in cohorts of patients with (Top) unilateral and bilateral, (Middle) bilateral, and (Bottom) hereditary retinoblastoma. Incidence in percentages with a 95% confidence interval in parentheses.
      For unilateral and bilateral retinoblastoma combined, the unadjusted chance of developing a trilateral retinoblastoma across all studies is 2.1% (95% confidence interval [CI]: 1.4%–2.8%; 18 cohorts), the chance of developing pineal trilateral retinoblastoma is 1.7% (95% CI: 1.2%–2.3%; 19 cohorts), and the chance of a nonpineal trilateral retinoblastoma is 0.4% (95% CI: 0.2%–0.6%; 18 cohorts). For bilateral retinoblastoma the chance of developing a trilateral retinoblastoma is 5.3% (95% CI: 3.3%–7.7%; 14 cohorts); restricting calculations to pineal trilateral retinoblastoma resulted in an incidence of 4.2% (95% CI: 2.6%–6.2%; 15 cohorts) and restricting to nonpineal trilateral retinoblastoma gave an incidence of 0.8% (95% CI: 0.4%–1.3%; 14 cohorts). In hereditary retinoblastoma we found a trilateral retinoblastoma incidence of 4.2% (95% CI: 1.6%–7.7%; 5 cohorts) and a pineal trilateral retinoblastoma incidence of 3.7% (95% CI: 1.8%–6.2%; 6 cohorts), and we did not calculate the nonpineal trilateral retinoblastoma incidence, as there were no cases in 5 retinoblastoma cohorts.

       Adjusted Estimates

      We adjusted for potential overestimation bias by restricting the analysis to cohorts that included at least 100 patients with retinoblastoma (Figure 1). We found incidences of 1.7% (95% CI: 1.2%–2.2%; 14 cohorts), 1.4% (95% CI: 1.0%–1.7%; 15 cohorts), and 0.3% (95% CI: 0.2%–0.6%; 14 cohorts) for any, pineal, and nonpineal trilateral retinoblastoma, respectively. In cohorts with only patient with bilateral retinoblastoma we found incidences of 3.8% (95% CI: 2.4%–5.4%; 10 cohorts), 2.9% (95% CI: 1.9%–4.2%; 11 cohorts) and 0.7% (95% CI: 0.3%–1.2%; 10 cohorts), respectively. Among patients with hereditary retinoblastoma we found a trilateral retinoblastoma incidence of 3.5% (95% CI: 1.2%–6.7%; 4 cohorts) and a pineal trilateral retinoblastoma incidence of 3.2% (95% CI: 1.4%–5.6%; 5 cohorts).

       Period Analysis

      To analyze changes over time we created 2 groups with the year 1995 as the cutoff year (depending on the midpoint of the study period). Before the year 1995 unadjusted trilateral retinoblastoma incidence for unilateral and bilateral retinoblastoma combined was 2.5% (95% CI: 1.5%–3.8%) vs 1.5% (95% CI: 0.9%–2.2%) from the year 1995 onward (P = .24). The incidence of pineal trilateral retinoblastoma before the year 1995 was 2.2% (95% CI: 1.3%–3.4%) vs 1.2% (95% CI: 0.8%–1.8%) from 1995 onward (P = .14).
      Restricted to patients with bilateral retinoblastoma, the unadjusted trilateral retinoblastoma incidence was 6.2% (95% CI: 3.2%–9.9%) before the year 1995 vs 3.7% (95% CI: 1.4%–6.9%) from the year 1995 onward (P = .44). The incidence of pineal trilateral retinoblastoma was 5.3% (95% CI: 2.7%–8.8%) before the year 1995 vs 2.9% (95% CI: 1.3%–5.1%) from the year 1995 onward (P = .38; Figure 3).

       Effect of Previous Therapy

      Four studies reported on trilateral retinoblastoma incidence in retinoblastoma cohorts who underwent previous systemic chemotherapy (Table 3). In a single-center study with 4 trilateral retinoblastoma cases an inverse association between chemotherapy and the development of pineoblastoma was reported (P = .014), with an incidence of 0.6% (1/180) and 8.6% (3/35), respectively, for patients who did and who did not receive previous chemotherapy for their retinoblastoma.
      • Ramasubramanian A.
      • Kytasty C.
      • Meadows A.T.
      • Shields J.A.
      • Leahey A.
      • Shields C.L.
      Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era.
      In a single-center study from the same center, but different period, 1 pineoblastoma was found in 18 hereditary patients with retinoblastoma who did not undergo chemotherapy, compared to none in 99 patients who did undergo chemotherapy.
      • Shields C.L.
      • Meadows A.T.
      • Shields J.A.
      • Carvalho C.
      • Smith A.F.
      Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma).
      However, in another single-center study with 3 trilateral retinoblastomas this association was reversed with an incidence of 1.9% (3/159) vs 0.0% (0/38), respectively (P > .99).
      • Chantada G.L.
      • Fandiño A.C.
      • Schvartzman E.
      • Raslawski E.
      • Schaiquevich P.
      • Manzitti J.
      Impact of chemoreduction for conservative therapy for retinoblastoma in Argentina.
      Three studies specifically looked at trilateral retinoblastoma incidence in cohorts of patients with retinoblastoma who underwent external beam radiotherapy (Table 3). In a single-center study with 4 trilateral retinoblastomas a pineal trilateral retinoblastoma incidence of 1.7% (3/179) was found in the group of patients with nonirradiated hereditary retinoblastoma and an incidence of 2.8% (1/36) was found in the irradiated group (P = .5).
      • Ramasubramanian A.
      • Kytasty C.
      • Meadows A.T.
      • Shields J.A.
      • Leahey A.
      • Shields C.L.
      Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era.
      • Ramasubramanian A.
      • Meadows A.T.
      • Shields J.A.
      • Leahey A.
      • Shields C.L.
      Reply to: incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era.
      A single-center study with 6 trilateral retinoblastomas found that patients with bilateral retinoblastoma who underwent irradiation as treatment for their retinoblastoma had a 6.2% (6/97) chance to develop trilateral retinoblastoma (5 pineal and 1 suprasellar); excluding the suprasellar tumor from the calculation resulted in a pineal trilateral retinoblastoma incidence of 5.2% (5/97).
      • Blach L.E.
      • McCormick B.
      • Abramson D.H.
      • Ellsworth R.M.
      Trilateral retinoblastoma–incidence and outcome: a decade of experience.
      Finally, in a single-center study with 5 cases a pineal trilateral retinoblastoma incidence of 5.7% (5/87) in patients with irradiated hereditary retinoblastoma was reported.
      • Imhof S.M.
      • Moll A.C.
      • Hofman P.
      • Mourits M.P.
      • Schipper J.
      • Tan K.E.
      Second primary tumours in hereditary- and nonhereditary retinoblastoma patients treated with megavoltage external beam irradiation.

       Risk of Bias and Study Quality Assessment

      Per-study scores on individual items of the risk-of-bias checklist (numbered from Q1 through Q6) can be found in Supplemental Table 2 (available at AJO.com), showing considerable risk of bias in terms of how much the cohort is population-like (Q1 and Q2) and the follow-up duration (Q4). To address assessment bias we compared trilateral retinoblastoma incidence in developed vs developing countries—the latter being potentially more prone to this type of bias, which would result in lower expected incidence numbers. This comparison indeed showed differences with unadjusted unilateral and bilateral trilateral retinoblastoma incidences of 2.3% (95% CI 1.6%–3.2%) vs 1.1% (95% CI 0.5%–1.9%; P = .32) and bilateral trilateral retinoblastoma incidences of 6.0% (95% CI 3.5%–9.2%) vs 2.6% (95% CI 0.4%–6.2%; P = .50) for developed and developing countries, respectively, though statistically not significantly different.

      Discussion

      This systematic review gives an overview of studies on trilateral retinoblastoma incidence. Our summary estimates (especially the adjusted ones) of trilateral retinoblastoma incidence in bilateral or hereditary retinoblastoma are considerably lower than previously summarized by Kivelä,
      • Kivelä T.
      Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma.
      with an estimated incidence ranging from 5% to 15% in bilateral retinoblastoma, reflecting small cohorts in earlier studies. Even the unadjusted trilateral retinoblastoma incidence from this meta-analysis is lower and more precise (relatively narrow confidence intervals) than generally assumed in “literature”; to test this we evaluated the trilateral retinoblastoma incidence mentioned in the introduction and discussion of articles included in the meta-analysis on survival after trilateral retinoblastoma
      • De Jong M.C.
      • Kors W.A.
      • de Graaf P.
      • Castelijns J.A.
      • Kivelä T.
      • Moll A.C.
      Trilateral retinoblastoma: a systematic review and meta-analysis.
      (for obvious reasons, we excluded articles that assessed trilateral retinoblastoma incidence) (Supplemental Table 3, available at AJO.com).
      The lower estimates for trilateral retinoblastoma incidence we calculated potentially reduce the cost-effectiveness of screening for trilateral retinoblastoma in patients with retinoblastoma beyond baseline imaging. More than 50% of trilateral retinoblastomas are diagnosed at the time of retinoblastoma diagnosis (with baseline magnetic resonance imaging of the eyes and brain), suggesting that baseline screening for trilateral retinoblastoma might indeed be useful.
      • De Jong M.C.
      • Kors W.A.
      • de Graaf P.
      • Castelijns J.A.
      • Kivelä T.
      • Moll A.C.
      Trilateral retinoblastoma: a systematic review and meta-analysis.
      The few studies that published on prior use of systemic chemotherapy and risk of developing trilateral retinoblastoma have shown conflicting results with respect to a potential decrease of trilateral retinoblastoma risk in patients with retinoblastoma. Whether intraarterial chemotherapy has an effect on the risk to develop trilateral retinoblastoma—theoretically improbable because systemic exposure to chemotherapy is very low—was only assessed in 1 relatively small cohort of 89 patients and does not allow for any conclusions on this issue.
      • Klufas M.A.
      • Gobin Y.P.
      • Marr B.
      • Brodie S.E.
      • Dunkel I.J.
      • Abramson D.H.
      Intra-arterial chemotherapy as a treatment for intraocular retinoblastoma: alternatives to direct ophthalmic artery catheterization.
      Also, the few studies that looked at prior radiotherapy did not allow for any meaningful meta-analysis. Should previous radiotherapy (commonly used before the year 1995) be inductive and previous chemotherapy (increasingly used since the year 1995) protective, then we would expect to see a clear reduction of trilateral retinoblastoma incidence over time. The estimated incidences did slightly decrease after the year 1995, but the differences were not statistically significant (Figure 3). Alternatively, larger cohort sizes in later studies could partially explain this difference.
      There is much heterogeneity between the studies reporting trilateral retinoblastoma incidence. Some studies looked at incidence data in a population (3 cohorts from 3 studies; see Table 1), but most are data from 1 or more (specialized) institutions, which—owing to referral bias—might have resulted in a higher trilateral retinoblastoma incidence, or maybe actually a lower incidence when children with trilateral retinoblastoma end up in different specialized pediatric neurooncology centers (Table 2). Also, some of the cohorts are from the same center. Other potential sources of heterogeneity are the choice of start date and end date (year) of the retinoblastoma cohort at risk, and loss to follow-up of patients in the cohort. The estimates in this study assume that of all patients with retinoblastoma in the cohort it is known whether they developed trilateral retinoblastoma, which might be considered appropriate because trilateral retinoblastoma develops relatively quickly (median interval 17 months) after retinoblastoma (since 1995 >95% are diagnosed with trilateral retinoblastoma before the age of 5 years).
      • De Jong M.C.
      • Kors W.A.
      • de Graaf P.
      • Castelijns J.A.
      • Kivelä T.
      • Moll A.C.
      Trilateral retinoblastoma: a systematic review and meta-analysis.
      There is a risk that patients with asymptomatic trilateral retinoblastoma without histopathologic proof of disease might have been false-positive trilateral retinoblastoma cases (eg, benign pineal cysts
      • Popovic M.B.
      • Balmer A.
      • Maeder P.
      • Braganca T.
      • Munier F.L.
      • Beck Popovic M.
      Benign pineal cysts in children with bilateral retinoblastoma: a new variant of trilateral retinoblastoma?.
      ), causing an overestimation of trilateral retinoblastoma incidence. On the other hand, patients with retinoblastoma, especially those from several decades back, might have died from central nervous system metastases that were not recognized as trilateral retinoblastoma (ie, false negatives).
      In summary the incidence of trilateral retinoblastoma is estimated to be substantially lower than previously reported in the literature concerning trilateral retinoblastoma, especially after adjusting for bias from small cohorts.
      Funding/support: M.C.d.J. was supported by the ODAS Foundation, Delft, The Netherlands. The author's work was independent of the funding organization. The funding organization had no involvement in the design or conduct of this study, data management and analysis, or manuscript preparation and review or authorization for submission. Financial disclosures: The following authors have no financial disclosures: Marcus C. De Jong, Wijnanda A. Kors, Pim De Graaf, Jonas A. Castelijns, Annette C. Moll, and Tero Kivela. All authors attest that they meet the current ICMJE criteria for authorship.

      Appendix

      Supplemental Table 1The Syntaxes Used to Obtain Articles That Reported Incidence of Trilateral Retinoblastoma With Pubmed and Embase
      Pubmed search syntax
      Both searches were performed on March 14, 2014 and updated on July 15, 2015.
      :
       (“Retinoblastoma”[Mesh] OR retinoblastoma[tw] OR retinoma[tw] OR retinocytoma[tw]) AND (“Pinealoma”[Mesh] OR pinealoma[tw] OR pineoblastoma[tw] OR pinealoblastoma[tw] OR pineal[tw] OR trilateral[tw] OR ectopic[tw] OR brain[tw] OR sellar[tw] OR suprasellar[tw] OR parasellar[tw]) AND ((“1966/01/01”[PDAT] : “3000/12/31”[PDAT]) AND (Dutch[lang] OR English[lang] OR German[lang])) NOT (“Animals”[Mesh] NOT “Humans”[Mesh])
      The Embase search syntax
      Both searches were performed on March 14, 2014 and updated on July 15, 2015.
      :
       (‘retinoblastoma’ OR ‘retinoblastoma’/exp OR retinoblastoma OR ‘retinoma’ OR ‘retinoma’/exp OR retinoma OR ‘retinocytoma’ OR ‘retinocytoma’/exp OR retinocytoma) AND (‘pinealoma’ OR ‘pinealoma’/exp OR pinealoma OR pineoblastoma OR ‘pinealoblastoma’ OR ‘pinealoblastoma’/exp OR pinealoblastoma OR pineal OR trilateral OR ectopic OR ‘brain’ OR ‘brain’/exp OR brain OR sellar OR suprasellar OR parasellar) AND [humans]/lim AND [embase]/lim AND ([dutch]/lim OR [english]/lim OR [german]/lim) AND [medline]/lim AND [1966–2015]/py
      a Both searches were performed on March 14, 2014 and updated on July 15, 2015.
      Supplemental Table 2Risk-of-Bias Assessment With a Modified Checklist by Hoy and Associates
      • Hoy D.
      • Brooks P.
      • Woolf A.
      • et al.
      Assessing risk of bias in prevalence studies: modification of an existing tool and evidence of interrater agreement.
      of the Studies That Assessed the Incidence of Trilateral Retinoblastoma and Were Included in This Systematic Review and Meta-analysis
      AuthorQ1Q2Q3Q4Q5Q6
      Amoaku et al
      • Amoaku W.M.
      • Willshaw H.E.
      • Parkes S.E.
      • Shah K.J.
      • Mann J.R.
      Trilateral retinoblastoma. A report of five patients.
      122021
      Antoneli et al
      • Antoneli C.B.G.
      • Ribeiro K.B.
      • Sakamoto L.H.
      • Chojniak M.M.
      • Novaes P.E.R.S.
      • Arias V.E.A.
      Trilateral retinoblastoma.
      202221
      Azar et al
      • Azar D.
      • Donaldson C.
      • Dalla-Pozza L.
      Questioning the need for routine bone marrow aspiration and lumbar puncture in patients with retinoblastoma.
      202000
      Bartuma et al
      • Bartuma K.
      • Pal N.
      • Kosek S.
      • Holm S.
      • All-Ericsson C.A.
      10-year experience of outcome in chemotherapy-treated hereditary retinoblastoma.
      000120
      Blach et al
      • Blach L.E.
      • McCormick B.
      • Abramson D.H.
      • Ellsworth R.M.
      Trilateral retinoblastoma–incidence and outcome: a decade of experience.
      000221
      Chantada et al
      • Chantada G.L.
      • Fandiño A.C.
      • Schvartzman E.
      • Raslawski E.
      • Schaiquevich P.
      • Manzitti J.
      Impact of chemoreduction for conservative therapy for retinoblastoma in Argentina.
      02201
      De Ioris et al
      • De Ioris M.A.
      • Valente P.
      • Randisi F.
      • et al.
      Baseline central nervous system magnetic resonance imaging in early detection of trilateral retinoblastoma: pitfalls in the diagnosis of pineal gland lesions.
      202021
      De Potter et al
      • De Potter P.
      • Shields C.L.
      • Shields J.A.
      Clinical variations of trilateral retinoblastoma: a report of 13 cases.
      002021
      Duncan et al
      • Duncan J.L.
      • Scott I.U.
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      002021
      Klufas et al
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      • Gobin Y.P.
      • Marr B.
      • Brodie S.E.
      • Dunkel I.J.
      • Abramson D.H.
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      000020
      Lim et al
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      Trilateral retinoblastoma.
      002021
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      002121
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      002021
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      002021
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      • Kuik D.J.
      • Hofman P.
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      22221
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      000021
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      • Klintworth G.
      Trilateral retinoblastoma: clinical and radiologic progression.
      002021
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      • Shields J.A.
      • Leahey A.
      • Shields C.L.
      Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era.
      • Ramasubramanian A.
      • Meadows A.T.
      • Shields J.A.
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      • Shields C.L.
      Reply to: incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era.
      000021
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      002021
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      • Smith A.F.
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      002020
      0 = high risk, 1 = intermediate risk, 2 = low risk.
      • Q1. Was the study's target population a close representation of the national population in relation to relevant variables? (Based on Marees et al.,
        • Marees T.
        • Moll A.C.
        • Imhof S.M.
        • de Boer M.R.
        • Ringens P.J.
        • van Leeuwen F.E.
        Risk of second malignancies in survivors of retinoblastoma: more than 40 years of follow-up.
        • Marees T.
        • van Leeuwen F.E.
        • de Boer M.R.
        • Imhof S.M.
        • Ringens P.J.
        • Moll A.C.
        Cancer mortality in long-term survivors of retinoblastoma.
        ie, 39.4% bilateral cases)
        • 0 points: proportion of bilateral deviates considerably (≥6 percentage points [%pts]) from population-like or undefined.
        • 1 point: proportion of bilateral deviates slightly (3–6 %pts) from population-like.
        • 2 points: proportion of bilateral population-like (<3 %pts).
      • Q2. Was the sampling frame a true or close representation of the target population? (eg, hospital-based: high risk, population-based: low risk)?
        • 0 points: hospital-based or undefined.
        • 2 point: national or regional population.
      • Q3. Was some form of random selection used to select the sample, OR was a census undertaken?
        • 0 points: selected cases (eg, based on type of therapy or undefined).
        • 2 points: consecutive cases.
      • Q4. Was the likelihood of patients missing from follow-up minimal? Was the length of the shortest prevalence period for the parameter of interest appropriate? (ie, adequate length of follow-up to observe the outcome)
        • 0 points: median follow-up <2.5 years or undefined.
        • 1 point: median follow-up ≥2.5 but <5 years.
        • 2 points: median follow-up ≥5 years.
      • Q5. Was an acceptable case definition used in the study?
        • 0 points: temporal clustering of cases with increasing follow-up or unclear.
        • 2 points: no evidence of temporal clustering of cases with increasing time period.
      • Q6. Was the way of trilateral retinoblastoma assessment appropriate (eg, histopathology, cerebrospinal fluid and on imaging: treatment response to therapy or disease progression)?
        • 0 points: undefined.
        • 1 point: clinical diagnosis including imaging.
        • 2 points: based on histopathology.
      Supplemental Table 3Trilateral Retinoblastoma Incidence Mentioned in the Introduction or Discussion of Articles Since 2000 Included in our Meta-analysis on Trilateral Retinoblastoma Survival,1 Excluding Articles That Assessed Trilateral Retinoblastoma Incidence
      StudyYearRetinoblastoma PopulationIncidence of Trilateral RetinoblastomaSource According to Authors
      Bonci et al22013Bilateral8%–10%Kivelä3
      Dai et al42008Unilateral or bilateral3%Bader et al,5 Amoaku et al,6 De Potter et al,7 Pesin et al8
      Dimaras et al92011Unilateral or bilateral3%De Potter et al7
      D’Elia et al102014Sporadic unilateral<0.5%De Potter et al7
      Sporadic bilateral5%–13%
      Familial bilateral5%–15%
      Dunkel et al112010Bilateral6%Blach et al12
      Huddleston et al132013Genetic form3%–9%Blach et al,12 Shields et al14
      Ibarra et al152000Unilateral0.5%Kingston et al,16 De Potter et al,7 Blach et al12
      Bilateral4%–10%
      James et al172010Unilateral or bilateral1.5%–5%Provenzale et al18
      Kamaleshwaran et al192014Sporadic unilateral<0.5%Kivelä3
      Sporadic bilateral5%–13%
      Familial bilateral5%–15%
      Kivela et al202003Hereditary5%–15%Kivelä,3 Kingston et al,16 Blach et al,12 De Potter et al7
      Raizis et al212013Unspecified<1%Antoneli et al22
      Rodjan et al232012Sporadic unilateral<0.5%De Potter et al,7 Kivelä3
      Sporadic bilateral5%–13%
      Familial bilateral5%–15%
      Popovic et al242006Unspecified4%–8%Kingston et al,16 De Potter et al,7 Shields et al25
      Popovic et al262007Sporadic unilateral<0.5%Kivelä3
      Sporadic bilateral5%–13%
      Familial bilateral5%–15%
      Shah et al272013All3%Shields et al28
      Unilateral0.5%
      Bilateral2%–11%
      Skrypnyk et al292004Unspecified5%De Potter et al7
      Tsuruta et al302011All3%De Potter et al7
      Wright et al312010Genetic form3%–9%Blach et al12
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      • 15.
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      • 19.
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      • 20.
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      Biography

      Marcus C. de Jong, MD, MSc, is a resident and PhD student at the department of Radiology and Nuclear Medicine at the VU University Medical Center, Amsterdam (the Netherlands). With a background in medicine and clinical epidemiology (he received both degrees from the Erasmus University Rotterdam) he has been working on various topics in the field of retinoblastoma (with a focus on the use of magnetic resonance imaging, but also on epidemiological topics) since 2012.