Journal of Investigative Dermatology Home

Increased Risk of Skin Cancer in 1,851 Long-Term Retinoblastoma Survivors

      Patients with hereditary retinoblastoma are at risk for developing cutaneous melanoma, but little is known about the role of sun exposure or other factors, and the incidence of nonmelanoma skin cancer (NMSC) is poorly understood. We investigated the incidence of melanoma and NMSC in a cohort of 1,851 White, long-term retinoblastoma survivors (1,020 hereditary and 831 nonhereditary) diagnosed during 1914‒2006. During follow-up through 2016, 33 hereditary and 7 nonhereditary survivors developed melanoma, and 26 hereditary and 9 nonhereditary survivors developed NMSC. Most NMSCs were on the head/neck, whereas melanomas were more broadly distributed with patterns similar to melanoma-prone families. For both outcomes, the median age at diagnosis was ~20 years younger among hereditary survivors than among nonhereditary survivors. At 50 years after retinoblastoma diagnosis, the cumulative incidence in hereditary survivors was 4.5% for melanoma and 3.7% for NMSC; for nonhereditary survivors, it was 0.7% and 1.5%, respectively. Sun sensitivity and phenotypic characteristics generally did not vary by skin cancer status. Hereditary retinoblastoma survivors have an increased risk for melanoma and NMSC that occurred earlier than that observed among nonhereditary survivors, likely reflecting genetic factors. These findings among White retinoblastoma survivors support consensus-based recommendations for skin cancer screening and sun protection starting at young ages and continuing long term.


      BCC (basal cell carcinoma), CI (confidence interval), NMSC (nonmelanoma skin cancer), RR (relative rate), SCC (squamous cell carcinoma), SIR (standardized incidence ratio)
      To read this article in full you will need to make a payment
      Purchase one-time access
      Society Members (SID/ESDR), remember to log in for access.
      Subscribe to Journal of Investigative Dermatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Abramson D.H.
        • Melson M.R.
        • Dunkel I.J.
        • Frank C.M.
        Third (fourth and fifth) nonocular tumors in survivors of retinoblastoma.
        Ophthalmology. 2001; 108: 1868-1876
        • Dommering C.J.
        • Marees T.
        • van der Hout A.H.
        • Imhof S.M.
        • Meijers-Heijboer H.
        • Ringens P.J.
        • et al.
        RB1 mutations and second primary malignancies after hereditary retinoblastoma.
        Fam Cancer. 2012; 11: 225-233
        • Fletcher O.
        • Easton D.
        • Anderson K.
        • Gilham C.
        • Jay M.
        • Peto J.
        Lifetime risks of common cancers among retinoblastoma survivors.
        J Natl Cancer Inst. 2004; 96: 357-363
      1. Fritz A. Percy C. Jack A. Shanmugaratnam K. Sobin L. Parkin D.M. International classification of diseases for oncology (ICD-O). World Health Organization, Geneva, Switzerland2000
        • Gooley T.A.
        • Leisenring W.
        • Crowley J.
        • Storer B.E.
        Estimation of failure probabilities in the presence of competing risks: new representations of old estimators.
        Stat Med. 1999; 18: 695-706
        • Gossai A.
        • Barton D.T.
        • Rees J.R.
        • Nelson H.H.
        • Karagas M.R.
        Keratinocyte cancers.
        in: Thun M.J. Linet M.S. Cerhan J.R. Haiman C.A. Schottenfeld D. Schottenfeld and Fraumeni: Cancer Epidemiology and Prevention. Oxford University Press, New York, NY2018: 1089-1118
        • Greene M.H.
        • Clark Jr., W.H.
        • Tucker M.A.
        • Elder D.E.
        • Kraemer K.H.
        • Guerry 4th, D.
        • et al.
        Acquired precursors of cutaneous malignant melanoma. The familial dysplastic nevus syndrome.
        N Engl J Med. 1985; 312: 91-97
        • Hatzistergos K.E.
        • Williams A.R.
        • Dykxhoorn D.
        • Bellio M.A.
        • Yu W.
        • Hare J.M.
        Tumor suppressors RB1 and CDKN2a cooperatively regulate cell-cycle progression and differentiation during cardiomyocyte development and repair.
        Circ Res. 2019; 124: 1184-1197
      2. Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, et al. SEER cancer statistics review, 1975-2016, National Cancer Institute,; 2019 (accessed July 8, 2021).

        • Kivelä T.
        • Asko-Seljavaara S.
        • Pihkala U.
        • Hovi L.
        • Heikkonen J.
        Sebaceous carcinoma of the eyelid associated with retinoblastoma.
        Ophthalmology. 2001; 108: 1124-1128
        • Kleinerman R.A.
        • Schonfeld S.J.
        • Sigel B.S.
        • Wong-Siegel J.R.
        • Gilbert E.S.
        • Abramson D.H.
        • et al.
        Bone and soft-tissue sarcoma risk in long-term survivors of hereditary retinoblastoma treated with radiation.
        J Clin Oncol. 2019; 37: 3436-3445
        • Kleinerman R.A.
        • Tucker M.A.
        • Sigel B.S.
        • Abramson D.H.
        • Seddon J.M.
        • Morton L.M.
        Patterns of cause-specific mortality among 2053 survivors of retinoblastoma, 1914–2016.
        J Natl Cancer Inst. 2019; 111: 961-969
        • Kleinerman R.A.
        • Tucker M.A.
        • Tarone R.E.
        • Abramson D.H.
        • Seddon J.M.
        • Stovall M.
        • et al.
        Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up.
        J Clin Oncol. 2005; 23: 2272-2279
        • Kleinerman R.A.
        • Yu C.L.
        • Little M.P.
        • Li Y.
        • Abramson D.
        • Seddon J.
        • et al.
        Variation of second cancer risk by family history of retinoblastoma among long-term survivors.
        J Clin Oncol. 2012; 30: 950-957
        • Lukowiak T.M.
        • Aizman L.
        • Perz A.
        • Miller C.J.
        • Sobanko J.F.
        • Shin T.M.
        • et al.
        Association of age, sex, race, and geographic region with variation of the ratio of basal cell to cutaneous squamous cell carcinomas in the United States.
        JAMA Dermatol. 2020; 156: 1192-1198
        • MacCarthy A.
        • Bayne A.M.
        • Brownbill P.A.
        • Bunch K.J.
        • Diggens N.L.
        • Draper G.J.
        • et al.
        Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951–2004.
        Br J Cancer. 2013; 108: 2455-2463
        • 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.
        J Natl Cancer Inst. 2008; 100: 1771-1779
        • Pappo A.S.
        • Armstrong G.T.
        • Liu W.
        • Srivastava D.K.
        • McDonald A.
        • Leisenring W.M.
        • et al.
        Melanoma as a subsequent neoplasm in adult survivors of childhood cancer: a report from the childhood cancer survivor study.
        Pediatr Blood Cancer. 2013; 60: 461-466
        • Preston D.
        • Lubin J.
        • Pierce D.
        • McConney M.
        • Shilnikova N.
        EPICURE risk regression and person-year computation software: command summary and user guide.
        Risk Sciences International, Ottawa2015
        • Sargen M.R.
        • Pfeiffer R.M.
        • Yang X.R.
        • Tucker M.A.
        • Goldstein A.M.
        Variation in cutaneous patterns of melanomagenesis according to germline CDKN2A/CDK4 status in melanoma-prone families.
        J Invest Dermatol. 2020; 140: 174-181.e3
        • Schonfeld S.J.
        • Kleinerman R.A.
        • Abramson D.H.
        • Seddon J.M.
        • Tucker M.A.
        • Morton L.M.
        Long-term risk of subsequent cancer incidence among hereditary and nonhereditary retinoblastoma survivors.
        Br J Cancer. 2021; 124: 1312-1319
        • Temming P.
        • Arendt M.
        • Viehmann A.
        • Eisele L.
        • Le Guin C.H.
        • Schündeln M.M.
        • et al.
        Incidence of second cancers after radiotherapy and systemic chemotherapy in heritable retinoblastoma survivors: a report from the German reference center.
        Pediatr Blood Cancer. 2017; 64: 71-80
        • Tonorezos E.S.
        • Friedman D.N.
        • Barnea D.
        • Bosscha M.I.
        • Chantada G.
        • Dommering C.J.
        • et al.
        Recommendations for long-term follow-up of adults with heritable retinoblastoma.
        Ophthalmology. 2020; 127: 1549-1557
        • Tucker M.A.
        • Elder D.E.
        • Curry M.
        • Fraser M.C.
        • Pichler V.
        • Zametkin D.
        • et al.
        Risks of melanoma and other cancers in melanoma-prone families over 4 decades.
        J Invest Dermatol. 2018; 138: 1620-1626
        • Tucker M.A.
        • Greene M.H.
        • Clark Jr., W.H.
        • Kraemer K.H.
        • Fraser M.C.
        • Elder D.E.
        Dysplastic nevi on the scalp of prepubertal children from melanoma-prone families.
        J Pediatr. 1983; 103: 65-69
        • Tucker M.A.
        • Halpern A.
        • Holly E.A.
        • Hartge P.
        • Elder D.E.
        • Sagebiel R.W.
        • et al.
        Clinically recognized dysplastic nevi. A central risk factor for cutaneous melanoma.
        JAMA. 1997; 277: 1439-1444
        • Watt T.C.
        • Inskip P.D.
        • Stratton K.
        • Smith S.A.
        • Kry S.F.
        • Sigurdson A.J.
        • et al.
        Radiation-related risk of basal cell carcinoma: a report from the Childhood Cancer Survivor Study.
        J Natl Cancer Inst. 2012; 104: 1240-1250