Although survival rates for childhood cancer have risen considerably, survivors remain at heightened risk for second malignant neoplasms (SMNs), with thyroid cancer being a notable concern. This study explores the demographic, clinical, genetic, and treatment-related profiles of childhood cancer survivors who developed thyroid cancer as a second or third malignancy, underscoring the necessity of extended long-term follow-up. Medical records of childhood cancer survivors treated from 1990 to 2018 who later presented with thyroid cancer as a second or third malignancy were retrospectively analyzed. Details on patient demographics, clinical features, treatment history, and outcomes were reviewed. In a cohort of 3204 childhood cancer survivors, 10 individuals (6 female, 4 male) were found to have papillary thyroid carcinoma (PTC) after a median latency of 9 years from their first cancer diagnosis. Radiation therapy, especially to the head and neck, had been administered in most cases. Genetic analysis detected mutations in the Cell Cycle Checkpoint Kinase 2 (CHEK2) and Adenomatous Polyposis Coli (APC) genes in four patients, potentially contributing to their increased susceptibility. Thyroid cancer was identified in all cases through ultrasound screening; all patients underwent total thyroidectomy, with three also receiving radioactive iodine (RAI) therapy. During a median follow-up of 5.5 years after the thyroid cancer diagnosis, no recurrences or PTC-related deaths occurred. Exposure to radiation therapy, particularly when combined with chemotherapy, substantially raises the likelihood of thyroid cancer in individuals who survived childhood cancer. Genetic predispositions further contribute to this risk. Ongoing lifelong monitoring for thyroid cancer is vital, above all for survivors who received radiation or chemotherapy. More research is warranted to improve surveillance protocols and to deepen understanding of the genetic influences on thyroid cancer development in this population. Timely identification and sustained observation are key to achieving a better long-term prognosis.
