ESPE Yearbook of Paediatric Endocrinology

J Clin Med. 2025 Jan 17;14(2):589. PMID: 39860595. doi: 10.3390/jcm14020589. [email protected]

Brief summary: This single-center retrospective review aimed to characterize thyroid cancer as a second or third malignant neoplasm (SMN) in childhood cancer survivors (CCSs) diagnosed between 1990 and 2018, as well as to identify potential risk factors that could inform tailored follow-up strategies.

Ten of 3,204 CCSs developed thyroid cancer between 4 and 19 years (median: 9 years) after the initial cancer diagnosis. All cases were histologically confirmed as papillary thyroid carcinoma. All patients were diagnosed through thyroid ultrasound and underwent total thyroidectomy, and 3 received radioactive iodine (RAI). No recurrences or deaths related to PTC occurred, with a median follow-up of 5.5 years after diagnosis. All patients had received chemotherapy, and 8 had also been treated with radiotherapy (RT). Genetic screening was performed in 6 of the 10 patients and revealed pathogenic variants in CHEK2, APC, and DICER1 genes in 3 individuals, possibly contributing to the increased risk; the remaining tests were negative.

Comment: The onset of second malignant neoplasms (SMNs) is a well-known long-term complication of childhood cancer and represents a leading cause of treatment-related mortality. Thyroid cancer accounts for up to 10% of SMNs and is one of the most common and clinically significant malignancies in CCSs. RT, chemotherapy with alkylating agents or anthracyclines, and targeted therapy with I-131 MIBG (metaiodobenzylguanidine) have all been described as risk factors for thyroid neoplasms. For RT in particular, a dose-dependent relationship has been demonstrated, with the highest relative risk observed at around 20Gy. Beyond this dose, the risk appears to decrease, likely due to radiation-induced thyroid cell death. Alongside these treatment-related factors, genetic predisposition is increasingly recognized as a contributing factor. Compared to previous studies, STC in this cohort appeared to occur earlier during follow-up, particularly in patients who had received RT. Alkylating agents and anthracyclines were identified as additional independent risk factors for STC. Therefore, all treatments, including I-131 MIBG, must be considered when assessing long-term risk in CCSs.

The risk of developing a second thyroid cancer necessitates careful long-term follow-up, to be initiated no later than 5 years after RT, as recommended by the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium. In this study, genetic testing revealed mutations in the Cell Cycle Checkpoint Kinase 2 (CHEK2) and Adenomatous Polyposis Coli (APC) genes, which may contribute to increased cancer risk. The authors emphasized the importance of genetic screening, which could help guide personalized follow-up strategies. The CHEK2 gene encodes a protein kinase involved in the DNA damage response, cell cycle checkpoint regulation, and maintenance of genomic stability. Mutations in CHEK2 compromise these critical cellular functions, leading to increased susceptibility to malignancies. Individuals with familial adenomatous polyposis, caused by pathogenic germline mutations in the APC gene, are at significantly increased risk of developing papillary thyroid cancer in addition to colorectal polyps.