The clinicopathologic and molecular profile of second primary thyroid cancer in pediatric cancer survivors

Abstract

To characterize the clinicopathological and molecular profiles, treatment, and outcomes of second primary thyroid cancer (SPTC) in childhood cancer survivors to inform risk-stratified surveillance and management. This retrospective case series enrolled patients (aged ≤18 years at thyroid cancer diagnosis) with SPTC at Beijing Children's Hospital (2016-2024). Inclusion required a history of childhood malignancy treated with radiotherapy and/or chemotherapy. Data on demographics, primary cancer, SPTC characteristics, treatment, outcomes and molecular alterations were collected. Twelve survivors with SPTC were included. The median age at primary cancer diagnosis was 4.3 years, with neuroblastoma/ganglioneuroblastoma (33.3%) and lymphoma (25.0%) being the most common. The median latency to SPTC diagnosis was 5.4 years. Most SPTCs (75.0%) were detected incidentally on surveillance imaging. Despite 75.0% presenting as T1-stage, the rate of lymph node metastasis (LNM) was notably high (75.0%). Molecular testing in six patients revealed diverse drivers, including a germline  TP53  mutation (Li-Fraumeni syndrome),  NTRK3 ,  ALK , and  RET  fusions, and a BRAF V600E mutation. At a median follow-up, half of patients were disease-free, 25.0% experienced recurrence, and one patient died. SPTC in childhood cancer survivors may represent a distinct entity characterized by early-stage presentation yet aggressive nodal spread and diverse genomic landscape. These findings highlight the potential value of comprehensive molecular testing for all such patients to identify occult cancer predisposition syndromes and actionable oncogenic alterations, facilitating personalized precision medicine. However, given the small sample size and incomplete molecular data, these findings require validation in larger prospective cohorts.