Second Tumors in Retinoblastoma Survivors

Part of the Essentials in Ophthalmology book series (ESSENTIALS)


Improvements in treatment over the past century have greatly increased survival for retinoblastoma patients. However, as survival has improved, second cancers have emerged as a major cause of morbidity and mortality in retinoblastoma survivors. Several large cohort studies of long-term survivors have consistently reported that hereditary survivors have a greater risk of second cancers compared to non-hereditary survivors, with elevated risks persisting into adulthood. The cumulative incidence of second cancers 50 years after retinoblastoma diagnosis is 36 % in hereditary survivors compared to only 6 % in non-hereditary survivors. The most common second cancers diagnosed in hereditary survivors are bone sarcomas, soft tissue sarcomas, and melanoma, which together account for 82 % of second cancers in these survivors. Increasing doses of radiation significantly increase the risk of bone and soft tissue sarcomas, but not melanoma. Chemotherapy in combination with radiotherapy increases the risk of bone sarcomas and soft tissue sarcomas, particularly leiomyosarcoma. Although radiotherapy is used less frequently in current treatment approaches for retinoblastoma, survivors previously treated with radiotherapy should be screened for the risk of second cancers into adulthood and encouraged to follow cancer prevention strategies. Further research is needed to evaluate second cancer risks associated with chemotherapies in current treatment approaches and identify potential genetic markers of risk.


Second primary cancer Retinoblastoma Sarcomas Radiotherapy 


Informed Consent and Conflict of Interest

Informed consent and animal studies disclosures are not applicable to this review.

Ruth Kleinerman, Lindsay Morton, Margaret Tucker, and Jeannette Wong declare that they have no conflict of interest.

This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute.

This work was presented at the conference “1914–2014: Celebrating 100 years of Our Retinoblastoma Center in New York,” September 18–19, 2014.


  1. Berrington de Gonzalez A, Kutsenko A, Rajaraman P. Sarcoma risk after radiation exposure. Clin Sarcoma Res. 2012;2(1):18. doi: 10.1186/2045-3329-2-18.CrossRefPubMedCentralPubMedGoogle Scholar
  2. Berrington de Gonzalez A, Gilbert E, Curtis R, Inskip P, Kleinerman R, Morton L, Rajaraman P, Little MP. Second solid cancers after radiation therapy: a systematic review of the epidemiologic studies of the radiation dose-response relationship. Int J Radiat Oncol Biol Phys. 2013;86(2):224–33. doi: 10.1016/j.ijrobp.2012.09.001.CrossRefPubMedGoogle Scholar
  3. Bhatia S, Sklar C. Second cancers in survivors of childhood cancer. Nat Rev Cancer. 2002;2(2):124–32. doi: 10.1038/nrc722.CrossRefPubMedGoogle Scholar
  4. Bosco EE, Knudsen ES. RB in breast cancer: at the crossroads of tumorigenesis and treatment. Cell Cycle. 2007;6(6):667–71.CrossRefPubMedGoogle Scholar
  5. Burkhart DL, Sage J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer. 2008;8(9):671–82. doi: 10.1038/nrc2399.CrossRefPubMedGoogle Scholar
  6. Dommering CJ, Marees T, van der Hout AH, Imhof SM, Meijers-Heijboer H, Ringens PJ, van Leeuwen FE, Moll AC. RB1 mutations and second primary malignancies after hereditary retinoblastoma. Fam Cancer. 2012;11(2):225–33. doi: 10.1007/s10689-011-9505-3.CrossRefPubMedCentralPubMedGoogle Scholar
  7. Eng C, Li FP, Abramson DH, Ellsworth RM, Wong FL, Goldman MB, Seddon J, Tarbell N, Boice Jr JD. Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst. 1993;85(14):1121–8.CrossRefPubMedGoogle Scholar
  8. Foster MC, Kleinerman RA, Abramson DH, Seddon JM, Tarone RE, Tucker MA. Tobacco use in adult long-term survivors of retinoblastoma. Cancer Epidemiol Biomarkers Prev. 2006;15(8):1464–8. doi: 10.1158/1055-9965.EPI-05-0783.CrossRefPubMedGoogle Scholar
  9. Francis JH, Kleinerman RA, Seddon JM, Abramson DH. Increased risk of secondary uterine leiomyosarcoma in hereditary retinoblastoma. Gynecol Oncol. 2012;124(2) :254–9. doi: 10.1016/j.ygyno.2011.10.019.CrossRefPubMedCentralPubMedGoogle Scholar
  10. Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986;323(6089):643–6. doi: 10.1038/323643a0.CrossRefPubMedGoogle Scholar
  11. Friend SH, Horowitz JM, Gerber MR, Wang XF, Bogenmann E, Li FP, Weinberg RA. Deletions of a DNA sequence in retinoblastomas and mesenchymal tumors: organization of the sequence and its encoded protein. Proc Natl Acad Sci U S A. 1987;84(24):9059–63.CrossRefPubMedCentralPubMedGoogle Scholar
  12. Gobin YP, Dunkel IJ, Marr BP, Brodie SE, Abramson DH. Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch Ophthalmol. 2011;129(6):732–7. doi: 10.1001/archophthalmol.2011.5.CrossRefPubMedGoogle Scholar
  13. Goldstein AM, Tucker MA. Dysplastic nevi and melanoma. Cancer Epidemiol Biomarkers Prev. 2013;22(4):528–32. doi: 10.1158/1055-9965.EPI-12-1346.CrossRefPubMedCentralPubMedGoogle Scholar
  14. Harbour JW, Lai SL, Whang-Peng J, Gazdar AF, Minna JD, Kaye FJ. Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science. 1988;241(4863):353–7.CrossRefPubMedGoogle Scholar
  15. Hawkins MM, Wilson LM, Burton HS, Potok MH, Winter DL, Marsden HB, Stovall MA. Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer. J Natl Cancer Inst. 1996;88(5):270–8.CrossRefPubMedGoogle Scholar
  16. Henderson TO, Rajaraman P, Stovall M, Constine LS, Olive A, Smith SA, Mertens A, Meadows A, Neglia JP, Hammond S, Whitton J, Inskip PD, Robison LL, Diller L. Risk factors associated with secondary sarcomas in childhood cancer survivors: a report from the childhood cancer survivor study. Int J Radiat Oncol Biol Phys. 2012;84(1):224–30. doi: 10.1016/j.ijrobp.2011.11.022.CrossRefPubMedCentralPubMedGoogle Scholar
  17. Howlader N, Noone AM, Krapcho M, Garshell J, Miller DH, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich A, Mariotti A, Lewis DR, Chen HS, Feurer EJ, Cronin KA. SEER Cancer Statistics Review, 1975–2011. 2011. Accessed Apr 2014.
  18. Kleinerman RA, Tarone RE, Abramson DH, Seddon JM, Li FP, Tucker MA. Hereditary retinoblastoma and risk of lung cancer. J Natl Cancer Inst. 2000;92(24):2037–9.CrossRefPubMedGoogle Scholar
  19. Kleinerman RA, Tucker MA, Tarone RE, Abramson DH, Seddon JM, Stovall M, Li FP, Fraumeni Jr JF. Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol. 2005;23(10):2272–9. doi: 10.1200/JCO.2005.05.054.CrossRefPubMedGoogle Scholar
  20. Kleinerman RA, Tucker MA, Abramson DH, Seddon JM, Tarone RE, Fraumeni Jr JF. Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma. J Natl Cancer Inst. 2007;99(1):24–31. doi: 10.1093/jnci/djk002.CrossRefPubMedGoogle Scholar
  21. Kleinerman RA, Schonfeld SJ, Tucker MA. Sarcomas in hereditary retinoblastoma. Clin Sarcoma Res. 2012a;2(1):15. doi: 10.1186/2045-3329-2-15.CrossRefPubMedCentralPubMedGoogle Scholar
  22. Kleinerman RA, Yu CL, Little MP, Li Y, Abramson D, Seddon J, Tucker MA. Variation of second cancer risk by family history of retinoblastoma among long-term survivors. J Clin Oncol. 2012b;30(9):950–7. doi: 10.1200/JCO.2011.37.0239.CrossRefPubMedCentralPubMedGoogle Scholar
  23. Knudson Jr AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971;68(4):820–3.CrossRefPubMedCentralPubMedGoogle Scholar
  24. Le Vu B, de Vathaire F, Shamsaldin A, Hawkins MM, Grimaud E, Hardiman C, Diallo I, Vassal G, Bessa E, Campbell S, Panis X, Daly-Schveitzer N, Lagrange JL, Zucker JM, Eschwege F, Chavaudra J, Lemerle J. Radiation dose, chemotherapy and risk of osteosarcoma after solid tumours during childhood. Int J Cancer. 1998;77(3):370–7.CrossRefPubMedGoogle Scholar
  25. Li FP, Abramson DH, Tarone RE, Kleinerman RA, Fraumeni Jr JF, Boice Jr JD. Hereditary retinoblastoma, lipoma, and second primary cancers. J Natl Cancer Inst. 1997;89(1):83–4.CrossRefPubMedGoogle Scholar
  26. Little MP, Schaeffer ML, Reulen RC, Abramson DH, Stovall M, Weathers R, de Vathaire F, Diallo I, Seddon JM, Hawkins MM, Tucker MA, Kleinerman RA. Breast cancer risk after radiotherapy for heritable and non-heritable retinoblastoma: a US-UK study. Br J Cancer. 2014;110(10):2623–32. doi: 10.1038/bjc.2014.193.CrossRefPubMedCentralPubMedGoogle Scholar
  27. MacCarthy A, Birch JM, Draper GJ, Hungerford JL, Kingston JE, Kroll ME, Onadim Z, Stiller CA, Vincent TJ, Murphy MF. Retinoblastoma in Great Britain 1963-2002. Br J Ophthalmol. 2009;93(1):33–7. doi: 10.1136/bjo.2008.139618.CrossRefPubMedGoogle Scholar
  28. MacCarthy A, Bayne AM, Brownbill PA, Bunch KJ, Diggens NL, Draper GJ, Hawkins MM, Jenkinson HC, Kingston JE, Stiller CA, Vincent TJ, Murphy MF. Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004. Br J Cancer. 2013;108(12):2455–63. doi: 10.1038/bjc.2013.228.CrossRefPubMedCentralPubMedGoogle Scholar
  29. Marees T, Moll AC, Imhof SM, de Boer MR, Ringens PJ, van Leeuwen FE. Risk of second malignancies in survivors of retinoblastoma: more than 40 years of follow-up. J Natl Cancer Inst. 2008;100(24):1771–9. doi: 10.1093/jnci/djn394.CrossRefPubMedGoogle Scholar
  30. Marees T, van Leeuwen FE, de Boer MR, Imhof SM, Ringens PJ, Moll AC. Cancer mortality in long-term survivors of retinoblastoma. Eur J Cancer. 2009;45(18):3245–53. doi: 10.1016/j.ejca.2009.05.011.CrossRefPubMedGoogle Scholar
  31. Marees T, van Leeuwen FE, Schaapveld M, Imhof SM, de Boer MR, Kors WA, Ringens PJ, Moll AC. Risk of third malignancies and death after a second malignancy in retinoblastoma survivors. Eur J Cancer. 2010;46(11):2052–8. doi: 10.1016/j.ejca.2010.03.029.CrossRefPubMedGoogle Scholar
  32. Morton LM, Onel K, Curtis RE, Hungate EA, Armstrong GT. The rising incidence of second cancers: patterns of occurrence and identification of risk factors for children and adults. Am Soc Clin Oncol Educ Book. 2014;2014:e57–67. doi: 10.14694/EdBook_AM.2014.34.e57.CrossRefGoogle Scholar
  33. Reulen RC, Frobisher C, Winter DL, Kelly J, Lancashire ER, Stiller CA, Pritchard-Jones K, Jenkinson HC, Hawkins MM. Long-term risks of subsequent primary neoplasms among survivors of childhood cancer. JAMA. 2011;305(22):2311–9. doi: 10.1001/jama.2011.747.CrossRefPubMedGoogle Scholar
  34. Rieder H, Lohmann D, Poensgen B, Fritz B, Aslan M, Drohm D, Strombach Angersbach FJ, Rehder H. Loss of heterozygosity of the retinoblastoma (RB1) gene in lipomas from a retinoblastoma patient. J Natl Cancer Inst. 1998;90(4):324–6.CrossRefPubMedGoogle Scholar
  35. Schwartz B, Benadjaoud MA, Clero E, Haddy N, El-Fayech C, Guibout C, Teinturier C, Oberlin O, Veres C, Pacquement H, Munzer M, N’Guyen TD, Bondiau PY, Berchery D, Laprie A, Hawkins M, Winter D, Lefkopoulos D, Chavaudra J, Rubino C, Diallo I, Benichou J, de Vathaire F. Risk of second bone sarcoma following childhood cancer: role of radiation therapy treatment. Radiat Environ Biophys. 2014;53(2):381–90. doi: 10.1007/s00411-013-0510-9.PubMedCentralPubMedGoogle Scholar
  36. Traboulsi EI, Zimmerman LE, Manz HJ. Cutaneous malignant melanoma in survivors of heritable retinoblastoma. Arch Ophthalmol. 1988;106(8):1059–61.CrossRefPubMedGoogle Scholar
  37. Tucker MA, D’Angio GJ, Boice Jr JD, Strong LC, Li FP, Stovall M, Stone BJ, Green DM, Lombardi F, Newton W, et al. Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med. 1987;317(10):588–93. doi: 10.1056/NEJM198709033171002. CrossRefPubMedGoogle Scholar
  38. Wong FL, Boice Jr JD, Abramson DH, Tarone RE, Kleinerman RA, Stovall M, Goldman MB, Seddon JM, Tarbell N, Fraumeni Jr JF, Li FP. Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA. 1997;278(15):1262–7.CrossRefPubMedGoogle Scholar
  39. Wong JR, Morton LM, Tucker MA, Abramson DH, Seddon JM, Sampson JN, Kleinerman RA. Risk of subsequent malignant neoplasms in long-term hereditary retinoblastoma survivors following chemotherapy and radiotherapy. J Clin Oncol. 2014;32(29):3284–90.CrossRefPubMedCentralPubMedGoogle Scholar
  40. Yu CL, Tucker MA, Abramson DH, Furukawa K, Seddon JM, Stovall M, Fraumeni Jr JF, Kleinerman RA. Cause-specific mortality in long-term survivors of retinoblastoma. J Natl Cancer Inst. 2009;101(8):581–91. doi: 10.1093/jnci/djp046.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Radiation Epidemiology Branch, Division of Cancer Epidemiology and GeneticsNational Cancer Institute, National Institutes of HealthRockvilleUSA
  2. 2.Human Genetics Program, Division of Cancer Epidemiology and GeneticsNational Cancer Institute, National Institutes of HealthRockvilleUSA

Personalised recommendations