title: The Incidence of Trilateral Retinoblastoma: A Systematic Review and Meta-Analysis.
abstract: OBJECTIVE
  To estimate the incidence of trilateral retinoblastoma in patients with retinoblastoma.
  
  
  METHODS
  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%).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, Netherlands. Electronic address: mc.dejong@vumc.nl.
authors.forename: Marcus C
authors.initials: MC
authors.lastname: de Jong
authors.affiliation: Department of Pediatric Oncology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Wijnanda A
authors.initials: WA
authors.lastname: Kors
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Pim
authors.initials: P
authors.lastname: de Graaf
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Jonas A
authors.initials: JA
authors.lastname: Castelijns
authors.affiliation: Department of Ophthalmology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Annette C
authors.initials: AC
authors.lastname: Moll
authors.affiliation: Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Tero
authors.initials: T
authors.lastname: Kivelä
mesh_terms: D014943:Global Health; D006801:Humans; D015994:Incidence; D019572:Retinal Neoplasms / Q000175:diagnosis / Q000453:epidemiology*; D012175:Retinoblastoma / Q000175:diagnosis / Q000453:epidemiology*