LAUSR

Simple Summary It is well-established that hereditary retinoblastoma survivors have a substantially increased risk of developing subsequent malignant neoplasms (SMNs). Although clinicians have long suspected that this population is also at increased risk for developing benign neoplasms, the evidence is unclear. Benign tumors can substantially impact health status and quality of life, while raising questions for clinicians, when faced with a mass in a retinoblastoma survivor. By 60 years following retinoblastoma diagnosis, 17.6% of hereditary survivors had developed a benign tumor, with lipomas and leiomyomas being the most frequently diagnosed types. Additionally, we report both an increased risk of benign tumors after SMNs and a reciprocal increased risk of SMNs after benign tumors among hereditary retinoblastoma survivors. If confirmed, the large magnitude of the absolute risks and the association between benign tumors and SMNs in this population may have implications for long-term surveillance. Abstract Hereditary retinoblastoma survivors have substantially increased risk of subsequent malignant neoplasms (SMNs). The risk of benign neoplasms, a substantial cause of morbidity, is unclear. We calculated the cumulative incidence of developing benign tumors at 60 years following retinoblastoma diagnosis among 1128 hereditary (i.e., bilateral retinoblastoma or unilateral with family history, mutation testing was not available) and 924 nonhereditary retinoblastoma survivors diagnosed during 1914–2006 at two US medical centers with follow-up through 2016. Using Cox proportional hazards regression, we compared benign tumor risk by hereditary status and evaluated the association between benign tumors and SMNs. There were 100 benign tumors among 73 hereditary survivors (cumulative incidence = 17.6%; 95% confidence interval [CI] = 12.9–22.8%) and 22 benign tumors among 16 nonhereditary survivors (cumulative incidence = 3.9%; 95%CI = 2.2–6.4%), corresponding to 4.9-fold (95%CI = 2.8–8.4) increased risk for hereditary survivors. The cumulative incidence after hereditary retinoblastoma was highest for lipoma among males (14.0%; 95%CI = 7.7–22.1%) and leiomyoma among females (8.9%; 95%CI = 5.2–13.8%). Among hereditary survivors, having a prior SMN was associated with 3.5-fold (95%CI = 2.0–6.1) increased risk of developing a benign tumor; the reciprocal risk for developing an SMN after a benign tumor was 1.8 (95%CI = 1.1–2.9). These large-scale, long-term data demonstrate an increased risk for benign tumors after hereditary versus nonhereditary retinoblastoma. If confirmed, the association between benign tumors and SMNs among hereditary patients may have implications for long-term surveillance.