Mediastinal Gamma-Delta T-Cell Lymphoblastic Lymphoma Successfully Treated With Chemotherapy Alone.

diagnosis of soft tissue sarcoma.2 We chose to review a relatively small cohort of children and adolescents, diagnosed with soft tissue sarcomas between 2006 and 2013 and registered in trials/registries by the German Cooperative Weichteilsarkom Studiengruppe (CWS), because their tumors had undergone rigorous reference histology review and cytogenic workup using newer technologies. Of 846 consecutive children and adolescents registered by the CWS between 2006 and 2013, 748 were eligible to be included in our analyses. The remaining 98 patients were excluded from the analyses, because histology review was unavailable or tumor cytogenetics were not conclusive. Twenty of 748 eligible patients had a prior history neoplasm; 14 of 748 eligible patients developed SNs. The 8-year cumulative incidence of SNs after a diagnosis of childhood soft tissue sarcoma was 4% in this cohort.2 By comparison, 20to 25-year cumulative incidence of second cancers after diagnosis of any type of childhood cancer was previously reported to range between 4.3% and 5.1%.3,4 Ngyuen et al1 stress the relatively high portion of sarcomas (14%) among second cancers diagnosed in survivors of childhood cancers, which was previously reported to range between 11% and 15.8%.5,6 In their comment on our study, Nguyen and colleagues compared the crude incidence of second sarcomas among 75,665 pediatric SEER patients diagnosed with any type of cancer and the crude incidence of second sarcomas among 748 pediatric CWS patients diagnosed with soft tissue sarcomas. Of note, only one secondary sarcoma was diagnosed in the CWS cohort. We strongly caution against calculating incidence rates based on a single case and without considering follow-up times and competing risks such as death. We note that Henderson et al5 previously analyzed second sarcoma risk among 14,372 participants in the Childhood Cancer Survivor Study; the cumulative incidence rate for the development of secondary sarcomas at 30 years after initial cancer diagnosis was 1.08%. Notably, 13 of 14 SNs in the CWS cohort developed in survivors of translocation-negative soft tissue sarcomas.2 This is in support of a previous study, which used the SEER database to demonstrate higher 10-year cumulative incidence of SMNs in 3963 children, adolescents and young adults surviving translocation-negative sarcomas (10-year cumulative SMN incidence 2.7%) compared with 4822 patients surviving translocation-positive sarcomas (10-year cumulative SMN incidence 2.1%).7 The CWS cohort, while being substantially smaller than the SEER cohort, offered highly reliable histology diagnoses and clear data on the presence/absence of known oncogenic translocations. Increased SMN rates in survivors of translocationnegative sarcomas could be influenced not only by exposure to chemotherapy or radiation, but also by germline variants in cancer predisposition genes. Tumor phenotypes/genotypes are likely to be impacted by monogenic and/or polygenic germline variants, and the relationship between sarcoma histology/cytogenetics and occurrence of other malignancies—including prior, concurrent and subsequent malignancies— may facilitate identification of those carrying relevant germline variants in cancer predisposition genes. In fact, patterns of multiple neoplasms were suggestive of NF1, TP53, DICER1, RB1 in 17 of 34 patients with multiple neoplasms in the CWS cohort. The patient reported by Nguyen and colleagues was diagnosed with hepatoblastoma and Ewing sarcoma at a very young age. This constellation does not point toward germline variants in specific germline genes. Genetic counseling was recommended by the treating physicians. Further studies are needed to understand the germline genetic underpinnings of cancer in children.