Genes and environment: effects on the development of second malignancies in retinoblastoma survivors

Abstract

Although it is a rare cancer, retinoblastoma has served as an important model in our understanding of genetic cancer syndromes. All patients with a germinal rb1 mutation possess a risk of the development of second malignancies. Approximately 40-50% of all retinoblastoma cases are considered germinal cases and recent work has indicated that nearly all retinoblastoma patients probably demonstrate a degree of mosaicism for the rb1 mutation, and thus are at risk of secondary malignancies. The risk of the development of these cancers continues throughout the patients' lives due to the loss of a functional RB1 protein and its critical tumor suppressive function in all cells. These cancers can develop in diverse anatomic locations, including the skull and long bones, soft tissues, nasal cavity, skin, orbit, brain, breast and lung. Treatments used for retinoblastoma such as external-beam radiation and chemotherapy can have a significant impact on the risk for and pattern of development of these secondary cancers. Second malignancies are the leading cause of death in germinal retinoblastoma survivors in the USA and thus continue to be an important subject of study in this patient population. Second malignancies following the germinal form of retinoblastoma are the subject of this review.Keywords cancer risk; external-beam radiation; germinal hereditary; pinealoblastoma; radiation-induced neoplasm; retinoblastoma; sarcoma; second malignancy; Survivor Epidemiology: incidence & survivalDuring the mid-20th Century, as treatment regimens for retinoblastoma improved, the number of survivors and their offspring began to increase. Treatment approaches for retinoblastoma in developed countries are now so effective that in the USA, Europe, and developed countries throughout the world, the leading cause of death among retinoblastoma survivors is not retinoblastoma itself, but second malignancies [1]. The incidence of second malignancies in survivors of retinoblastoma who carry the rb1 mutation has been reviewed extensively [1][2][3][4][5][6][7][8][9][10][11][12][13]. Cumulative incidence reports of second malignancies have varied, at least in part because of the wide range in design and population size of these reports. Most large studies with adequate long-term follow-up have reported incidence rates of approximately 0.5-1 % per year when a constant risk of cancer development per year of survival is calculated based on reported cumulative risk rates [1,3,7,10,14]. The study with †

Sinonasal adenocarcinoma: A rare second malignancy in long term retinoblastoma survivors

“…Among patients with hereditary retinoblastoma patients surviving more than 40 years after retinoblastoma diagnosis, more than half of the absolute excess risk could be attributed to epithelial cancers 4. External beam radiation therapy is a contributory factor in the development of additional tumors in retinoblastoma survivors 11–13. Our patients received radiation therapy as a part of their treatment and developed sinonasal adenocarcinoma as a second malignancy.…”

Craniofacial second primary tumors in patients with germline retinoblastoma previously treated with external beam radiotherapy: A retrospective institutional analysis

“…Furthermore, there is no evidence that the specific type and site of the RB1 genetic alteration could also affect the development of craniofacial SPT in the irradiated field of germline retinoblastoma patients . Whether other phenomena, such as epigenetic factors, could explain this relationship remain unclear.…”

Recent advancements in the management of retinoblastoma and uveal melanoma

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