An Increased Risk of Second Malignant Neoplasms After Rhabdomyosarcoma: Population‐Based Evidence for a Cancer Predisposition Syndrome?

Abstract

Background Rhabdomyosarcoma survivors have an increased risk of developing second malignant neoplasms (SMN); this risk is traditionally attributed to the effects of multidisciplinary management required for cure. However, the impact of constitutional predisposition has not been properly analyzed. Methods We analyzed the risk of SMN among 1,151 children diagnosed with rhabdomyosarcoma and reported to the Surveillance, Epidemiology, and End Results registries (SEER‐9) from 1973 to 2010. Standardized incidence ratios (SIR) and corresponding 95% confidence intervals (CI) were calculated using SEERStat 8.1.2. Results Children with pleomorphic and embryonal rhabdomyosarcoma had an increased risk of developing a SMN (SIR = 15.77, 95%CI 1.91–56.96 and SIR = 5.6, 95%CI 3.32–8.85, respectively). The risk was age‐dependent; the highest was among children <2 years (SIR = 13.38, 95%CI 4.34–31.22) and the lowest was in children >10 years (SIR = 3.35, 95%CI 1.53–6.35). The risk for the youngest patients was higher for those with embryonal rhabdomyosarcoma (SIR = 14.72, 95%CI 4.01–37.70) compared to other histiotypes. Additionally, the risk of SMN was independent of the use of radiation to the primary (SIR = 6.50, 95%CI 3.97–10.03 and SIR = 4.57, 95%CI 2.09–8.68, for children receiving and not receiving radiation, respectively). The pattern of SMN observed was consistent with the Li‐Fraumeni spectrum. Conclusions Children with rhabdomyosarcoma are at high risk of developing SMN. This risk is higher for a subgroup of young children with pleomorphic and embryonal histologies, and is independent of the use of radiation. This suggests that a subgroup of children with pleomorphic and embryonal rhabdomyosarcoma may have a constitutional cancer predisposition. Pediatr Blood Cancer 2015; 9999:1–6 © 2015 Wiley Periodicals, Inc.

Second primary cancers in people who had cancer as children: an Australian Childhood Cancer Registry population‐based study

“…The greatest relative risk of second primary cancers in our study was for people diagnosed with rhabdomyosarcoma during childhood; the SIR of 19.9 was much higher than the 5.7 estimated by a United States study that included people diagnosed with rhabdomyosarcomas before the age of 19 years during 1973-2010. 19 However, the authors of the American study noted that most of the second cancers identified were in people with first primary rhabdomyosarcoma diagnoses during 2000-2010; restricting analysis to these cases resulted in a SIR of 21, similar to our figure. Without explaining the recent sharp rise in relative risk for people diagnosed with childhood rhabdomyosarcoma, the authors suggested that they may be genetically predisposed to cancer, adding to the effects of exposure to chemotherapy and radiotherapy while young.…”

“…Without explaining the recent sharp rise in relative risk for people diagnosed with childhood rhabdomyosarcoma, the authors suggested that they may be genetically predisposed to cancer, adding to the effects of exposure to chemotherapy and radiotherapy while young. 19 Endocrine system-related second primary cancers were relatively frequent among 5-year survivors in our study, particularly thyroid and breast cancers. Radiotherapy is the only risk factor for subsequent development of these two solid cancer types supported by strong clinical evidence.…”

“…However, the authors of the American study noted that most of the second cancers identified were in people with first primary rhabdomyosarcoma diagnoses during 2000–2010; restricting analysis to these cases resulted in a SIR of 21, similar to our figure. Without explaining the recent sharp rise in relative risk for people diagnosed with childhood rhabdomyosarcoma, the authors suggested that they may be genetically predisposed to cancer, adding to the effects of exposure to chemotherapy and radiotherapy while young …”

Somatic and Germline TP53 Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors

“…Patient 1 did not harbor a germline mutation in a tumor suppressor gene, but epidemiologic data suggest that children diagnosed with rhabdomyosarcoma (embryonal and pleomorphic subtypes) have heightened risk of developing SMNs (50). Clearly the molecular basis for SMN risk remains to be defined for many pediatric cancer survivors.…”

Second malignancy risk among pediatric, adolescent, and young adult survivors of fusion‐positive and fusion‐negative sarcomas: Results from the SEER database, 1992 through 2012

“…4 Nevertheless, published reports have suggested that Ewing sarcomas (F 1 sarcomas) are not represented among the spectrum of sarcomas diagnosed in TP53 mutation carriers. 5 In addition, our recently published work indicates that individuals with alveolar rhabdomyosarcoma (mostly F 1 soft-tissue sarcomas) are less likely to have a first-degree relative with cancer 6 or to develop a second malignancy 7,8 compared with those with embryonal or pleomorphic rhabdomyosarcoma (F-soft tissue sarcomas).…”