• M. OrjuelaEmail author
Part of the Pediatric Oncology book series (PEDIATRICO)


From an epidemiologic perspective, retinoblastoma is one of the most interesting childhood tumors to study. Retinoblastoma is a primitive neuroectodermal tumor, and its occurrence in early childhood suggests that incidence can be associated with events affecting development of neuroectodermal tissues during the fetal period. Furthermore, it exists in two genetically distinct forms associated with differing (though not mutually exclusive) clinical presentations (see chapters 3 and 4). This allows the formulation of two distinct, though parallel, mechanisms for disease development. Additionally, there is considerable geographic variation in incidence, suggesting differential genetic susceptibility or environmental exposure(s). The combination of these three factors: a defined and relatively limited temporal window for development; two genetically distinct forms arriving, via different genetic pathways, to essentially identical histologic presentations; and the geographic variation in incidence suggest several handles/angles through which one could examine associations and risk factors for development of this disease. Despite these facts, and due in large part to the rarity of the disease, little is understood about the factors that culminate in the relatively well understood cell cycle and apoptotic pathway defects that define retinoblastoma at a molecular level.

Much has been published regarding the molecular changes that occur during the development of retinoblastoma, and recently, more reports have become available regarding incidence, survival, and treatment in countries outside of northern North America and Europe. Results from these studies point to some potential risk factors underlying disease development; however, few studies have been done to specifically elucidate these factors. Thus, this discussion of the epidemiology of retinoblastoma will, out of necessity, focus on disease incidence and on those few hypo­theses that have been explored using population based study methodology.


Human Papilloma Virus Primitive Neuroectodermal Tumor Bilateral Disease Unilateral Disease Human Papilloma Virus Status 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The author gratefully acknowledges the assistance of Aisha Siebert, MPH, and of Drs M. Veronica Ponce, Arturo Fajardo Gutierrez, A. Krishnakumar, and Desiree Debling, who generously shared data in advance of publication. In addition, the author is appreciative for assistance from Dr M. ­Ramirez Ortiz, and Dr W. Gauss. This work was supported in part by NIH 1 R01 CA98180 and ACS RSG CNE-104953.


  1. Bhurgri Y, Muzaffar S, Ahmed R, Ahmed N, Bhurgri H, Usman A, Faridi N, Malik J, Kazi LA, Bashir I, Kayani N, Bhurgri A, Pervez S, Hasan SH, Soomro AH (2004) Retinoblastoma in Karachi, Pakistan. Asian Pac J Cancer Prev 5:159-163PubMedGoogle Scholar
  2. Bradbury BD, Jick H (2004) In-vitro fertilization and childhood retinoblastoma. Br J Clin Pharmacol 58:209-211PubMedCrossRefGoogle Scholar
  3. Bruinsma F, Venn A, Lancaster P, Speirs A, Healy D (2000) Incidence of cancer in children born after in-vitro fertilization. Hum Reprod 15:604-607PubMedCrossRefGoogle Scholar
  4. Bunin GR, Buckley JD, Boesel CP, Rorke LB, Meadows AT (1994) Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the Children’s Cancer Group. Cancer Epidemiol Biomarkers Prev 3:197-204PubMedGoogle Scholar
  5. Bunin GR, Kuitjen RR, Buckley JD, Rorke LB, Meadows AT (1993) Relation between maternal diet and subsequent primitive neuroectodermal brain tumors in young children. N Engl J Med 329:536-541PubMedCrossRefGoogle Scholar
  6. Bunin GR, Meadows AT, Emanuel BS, Bucly JD, Woods WG, Hammond GD (1989) Pre- and post-conception factors associated with heritable and non-heritable retinoblastoma. Cancer Res 49:5730-5735PubMedGoogle Scholar
  7. Bunin GR, Petrakova A, Meadows AT, Emanuel BS, Buckley JD, Woods WG, Hammond GD (1990) Occupations of parents of the children with retinoblastoma: a report from the Children’s Cancer Study Group. Cancer Res 50:7129-7133PubMedGoogle Scholar
  8. Butros LJ, Abramson DH, Dunkel IJ (2002) Delayed diagnosis of the retinoblastoma: analysis of degree, cause, and potential consequences. Pediatrics 109:e45PubMedCrossRefGoogle Scholar
  9. Chantada G, Fandino A, Manzitti J, Urrutia L, Schvartzman E (1999) Late diagnosis of retinoblastoma in a developing country. Arch Dis Child 80:171-174PubMedCrossRefGoogle Scholar
  10. Cordier S, Mandereau L, Preston-Martin S, Little J, Lubin F, Mueller B, Holly E, Filippini G, Peris-Bonet R, McCredie M, Choi NW, Arsla A (2001) Parental occupations and childhood brain tumors: result of an international case-control study. Cancer Causes Control 12:865-874PubMedCrossRefGoogle Scholar
  11. de Aguirre Neto JC, Antoneli CB, Ribeiro KB, Castilho MS, Novaes PE, Chojniak MM, Arias V (2007) Retinoblastoma in children older than 5 years of age. Pediatr Blood Cancer 48:292-295PubMedCrossRefGoogle Scholar
  12. Dockerty JD, Draper G, Vincent T, Rowan SD, Bunch KJ (2001) Case-Control study of parental age, parity and socioeconomic level in relation to childhood cancers. Int J Epidemiol 30:1428-1437PubMedCrossRefGoogle Scholar
  13. Dryja TP, Mukai S, Rapaport JM, Yandell DW (1989) Parental origin of mutations of the retinoblastoma gene. Nature 339:556-558PubMedCrossRefGoogle Scholar
  14. Erwenne CM, Franco EL (1989) Age and lateness of referral as determinant of extra ocular retinoblastoma. Ophthalmic Paediatr Genet 10:179-184PubMedCrossRefGoogle Scholar
  15. Fajardo-Gutiérrez A, Juárez-Ocaña S, González-Miranda G, Palma-Padilla V, Carreón-Cruz R, Ortega-Álvarez MC, Mejía-Arangure JM (2007) Incidence of cancer in children residing in ten jurisdictions of the Mexican republic: Importance of the Cancer registry (a population-based study). BMC Cancer 19:7-68Google Scholar
  16. French AE, Grant R, Weitzman S, Ray JG, Vermeulen MJ, Sung L, Greenberg M, Koren G (2003) Folic acid food fortification is associated with a decline in neuroblastoma. Clin Pharmacol Ther 74:288-294PubMedCrossRefGoogle Scholar
  17. Gillison ML, Chen R, Goshu E, Rushlow D, Chen N, Banister C, Creek KE, Gallie BL (2007) Human retinoblastoma is not caused by known pRb-inactivating human DNA tumor viruses. Int J Cancer 120:1482-1490PubMedCrossRefGoogle Scholar
  18. Goddard A, Kingston JE, Hungerford JL (1999) Delay in diagnosis of retinoblastoma: risk factors and treatment outcome. Br J Ophthalmol 832:1320-1323CrossRefGoogle Scholar
  19. Hiyama E, Iehara T, Sugimoto T, Fukuzawa M, Hayashi Y, Sasaki F, Sugiyama M, Kondo S, Yoneda A, Yamaoka H, Tajiri T, Akazawa K, Ohtaki M (2008) Effectiveness of screening for neuroblastoma at 6 months of age: a retrospective population-based cohort study. Lancet 371:1173-1180PubMedCrossRefGoogle Scholar
  20. Holly EA, Bracci PM, Mueller BA, Preston-Martin S (1998) Farm and animal exposures and pediatric brain tumors. Cancer Epidemiol Biomarkers Prev 7:797-802PubMedGoogle Scholar
  21. Hooper ML (1999) Is sunlight an aetiological agent in the genesis of retinoblastoma? Br J Cancer 79:1273-1276PubMedCrossRefGoogle Scholar
  22. Jemal A, Devesa SS, Fears TE, Fraumeni JF Jr (2000) Retinoblastoma incidence and sunlight exposure. Br J Cancer 82:1875-1878PubMedCrossRefGoogle Scholar
  23. Kato MV, Ishizaki K, Shimizu T, Ejima Y, Tanooka H, Takayama J, Kaneko A, Toguchida J, Sasaki MS (1994) Parental origin of germ-line and somatic mutations in the retinoblastoma gene. Hum Genet 94:31-38PubMedCrossRefGoogle Scholar
  24. Khandekar R, Ganesh A, Lawati J (2004) A 12-year epidemiological review of retinoblastoma in Omani children. Ophthalmic Epidemiol 11:151-159PubMedCrossRefGoogle Scholar
  25. Kristensen P, Andersen A, Irgens LM, Bye AS, Sundheim L (1996) Cancer in offspring of parents engaged in agricultural activities in Norway: incidence and risk factors in the farm environment. Int J Cancer 65:39-50PubMedCrossRefGoogle Scholar
  26. Lanier AP, Holck P, Ehrsam Day G, Key C (2003) Childhood cancer among Alaska Natives. Pediatrics 112:e369CrossRefGoogle Scholar
  27. Lidegaard O, Pinbrog A, Andersen AN (2005) Imprinting diseases and IVF: Danish National IVF cohort study. Hum Reprod 20:950-954PubMedCrossRefGoogle Scholar
  28. MacCarthy A, Draper GJ, Steliarova-Foucher E, Kingston JE (2006) Retinoblastoma incidence and survival in European children (1978-1997). Report from the Automated Childhood Cancer Information System project. Eur J Cancer 42:2092-2102Google Scholar
  29. Maris JM (2007) Neuroblastoma. Lancet 369:2106-2120PubMedCrossRefGoogle Scholar
  30. Maris JM, Woods WG (2008) Screening for neuroblastoma: a resurrected idea? Lancet 371:1142-1143PubMedCrossRefGoogle Scholar
  31. Mohan A, Venkatesan N, Kandalam M, Pasricha G, Acharya P, Khetan V, Gopal L, Sharma T, Biswas J, Krishnakumar S (2009) Detection of human papillomavirus DNA in retinoblastoma samples: a preliminary study. J Pediatr Hematol Oncol 31:8-13Google Scholar
  32. Moll AC, Imhof SM, Kuik DJ, Bouter LM, Den Otter W, Bezemer PD, Koten JW, Tan KE (1996) High parental age is associated with sporadic hereditary retinoblastoma: the Dutch Retinoblastoma Register 1862-1994. Hum Genet 98:109-112PubMedCrossRefGoogle Scholar
  33. Moll AC, Imhof SM, Cruysberg JR, Shouten-Van Meeteren AY, Boers M, Van Leeuwen FE (2003) Incidence of retinoblastoma in children born after in-vitro fertilization. Lancet 361:309-310PubMedCrossRefGoogle Scholar
  34. Montoya-Fuentes H, de la Paz Ramirez-Munoz M, Villar-Calvo V, Suarez-Rincon AE, Ornelas-Aguirre JM, Vazquez-Camacho G, Orbach-Arbouys S, Bravo-Cuellar A, Sanchez-Corona J (2003) Identification of DNA sequences and viral proteins of 6 human papilloma virus types in retinoblastoma tissue. Anticancer Res 23:2853-2862PubMedGoogle Scholar
  35. Olshan AF, De Roos AJ, Teschke K, Neglia JP, Stram DO, Pollock BH, Castleberry RP (1999) Neuroblastoma and parental occupation. Cancer Causes Control 10:539-549PubMedCrossRefGoogle Scholar
  36. Olshan AF, Smith JC, Bondy ML, Neglia JP, Pollock BH (2002) Maternal vitamin use and reduced risk of neuroblastoma. Epidemiology 13:575-580PubMedCrossRefGoogle Scholar
  37. Orjuela M, Castaneda VP, Ridaura C, Lecona E, Leal C, Abramson DH, Orlow I, Gerald W, Cordon-Cardo C (2000a) Presence of human papilloma virus in tumor tissue from children with retinoblastoma: an alternative mechanism for tumor development. Clin Cancer Res 6:4010-4016PubMedGoogle Scholar
  38. Orjuela M, Lecona E, Salazar A, Leal C, Abramson D, Mueller N (2000) Risk factors for the development of sporadic retinoblastoma in Mexico. In: Proceedings of the 91st annual meeting of the American association for cancer research, 2298Google Scholar
  39. Orjuela MA, Titievsky L, Liu X, Ramirez-Ortiz M, Ponce-Castaneda V, Lecona E, Molina E, Beaverson K, Abramson DH, Mueller NE (2005) Fruit and vegetable intake during pregnancy and risk for development of sporadic retinoblastoma. Cancer Epidemiol Biomarkers Prev 14:1433-1440PubMedCrossRefGoogle Scholar
  40. Ozdemir H, Tacyildiz N, Unal E, Yavuz G, Ugur H, Gunduz K (2007) Clinical and epidemiological characteristics of retinoblastoma: correlation with Prognosis in a Turkish pediatric oncology center. Pediatr Hematol Oncol 24:221-231PubMedCrossRefGoogle Scholar
  41. Ozkan A, Pazarli H, Celkan T, Karaman S, Apak H, Kaner G, Uzel O, Yildiz I (2006) Retinoblastoma in Turkey: survival and clinical characteristics 1981-2004. Pediatr Int 48:369-373PubMedCrossRefGoogle Scholar
  42. Palazzi MA, Yunes JA, Cardinalli IA, Stangehaus GP, Brandalise SR, Ferriera SA, Sobrinho JSP, Villa LL (2003) Detection of oncogenic human papillomavirus in sporadic retinoblastoma. Acta Ophthalmol Scand 81:396-398PubMedCrossRefGoogle Scholar
  43. Parkin DM, Kramarova E, Draper GJ, Masuyer E, Michaelis J, Neglia JP, Qureshi S, Stiller CA (1998) International incidence of childhood cancer. International Agency for Research on Cancer, Lyon, FranceGoogle Scholar
  44. Preston-Martin S, Lewis S, Winkelmann R, Borman B, Auld J, Pearce N (1993) Descriptive epidemiology of primary cancer of the brain, cranial nerves, and cranial meninges in New Zealand 1948-1988. Cancer Causes Control 4:529-538PubMedCrossRefGoogle Scholar
  45. Ponce-Castneda MV, Torres-Lopez J, Burgueno-Ferreira J, Bravo JC, Ramon G, Hernandez-Angeles A, Fernandez-Mendez K, Leon-Garcia D, Bautista-DeLucio VM, Ramierz-Ortiz M, Cabrera-Munoz ML, Sadowinky-Pine S, Ramirez J, Coello G, Mendoza-Rodriguez V, Lopez-Casillas F, Orjuela M (2008) Molecular evidence implicating HPV involvement in human retinoblastoma pathogenesis. In: Proceedings of ISGEDR 2008Google Scholar
  46. Schilling FH, Spix C, Berthold F, Erttmann R, Fehse N, Hero B, Klein G, Sander J, Schwarz K, Treuner J, Zorn U, Michaelis J (2002) Neuroblastoma screening at one year of age. N Engl J Med 346:1047-1053PubMedCrossRefGoogle Scholar
  47. Seregard S, Lundell G, Svedberg H, Kivela T (2004) Incidence of retinoblastoma from 1958 to 1998 in Northern Europe: advantages of birth control analysis. Ophthalmology 111:1228-1232Google Scholar
  48. Sivakumaran TA, Ghose S, Kumar HAS, Kucheria K (2000) Parental age in Indian patients with sporadic hereditary retinoblastoma. Ophthalmic Epidemiol 7:285-291PubMedCrossRefGoogle Scholar
  49. Stiller CA, Parkin DM (1996) Geographic and ethnic variations in the incidence of childhood cancer. Br Med Bull 52:682-703PubMedCrossRefGoogle Scholar
  50. Swaminathan R, Rama R, Shanta V (2008) Childhood Cancer in Chennai, India, 1990-2001: incidence and survival. Int J Cancer 122:2607-2611PubMedCrossRefGoogle Scholar
  51. Wallach M, Balmer A, Munier F, Houghton S, Pampallona S, von der Weid N, Beck-Popovic M (2006) Shorter Time to Diagnosis and Improved Stage at Presentation in Swiss Patients With Retinoblastoma Treated From 1963 to 2004. Pediatrics 118:e1493-e1498PubMedCrossRefGoogle Scholar
  52. Woods WG, Gao RN, Shuster JJ, Robison LL, Bernstein M, Weitzman S, Bunin G, Levy I, Brossard J, Dougherty G, Tuchman M, Lemieux B (2002) Screening of infants and mortality due to neuroblastoma. N Engl J Med 346:1041-1046PubMedCrossRefGoogle Scholar
  53. Yamamoto K, Ohta S, Ito E, Hayashi Y, Asami T, Mabuchi O, Higashigawa M, Tanimura M (2002) Marginal decrease in mortality and marked increase in incidence as a result of neuroblastoma screening at 6 months of age: cohort study in seven prefectures in Japan. J Clin Oncol 20:1209-1214PubMedCrossRefGoogle Scholar
  54. Yip BH, Pawitan Y, Czene K (2006) Parental age and risk of childhood cancers: a population-based cohort study from Sweden. Int J Epidemiol 35:1495-1503Google Scholar
  55. Zhu X, Dunn J, Philips R, Goddard A, Paton K, Becker A, Gallie B (1989) Preferential germ line mutation of the paternal alley in retinoblastoma. Nature 340:312-313PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Columbia UniversityNYUSA

Personalised recommendations