{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T15:02:27Z","timestamp":1785855747768,"version":"3.56.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T00:00:00Z","timestamp":1737676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>High-risk differentiated thyroid cancer in 2015 American Thyroid Association risk stratification system (ATA-RSS) exhibits a significantly increased probability of recurrence and poor outcomes. This study aimed to investigate the molecular profiles of high-risk differentiated thyroid cancer and to assess the role of molecular testing in enhancing prognostic risk stratification.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In a single-center study conducted at Fujian Cancer Hospital, Fujian Province, China, a consecutive cohort of differentiated thyroid cancer patients identified as high-risk under 2015 ATA-RSS criteria were retrospectively assessed, spanning from November 1, 2019, to March 31, 2022. Molecular characterize groups were conducted using an 18-gene next-generation sequencing assay. Patients harboring mutations in the <jats:italic>TERT<\/jats:italic> promoter, <jats:italic>TP53<\/jats:italic>, or <jats:italic>PIK3CA<\/jats:italic> genes were categorized as the high molecular risk group, while all others were assigned to the non-high molecular risk group.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among the 108 cases, 32 (29.6%) fell into the high molecular risk group, characterized by a significantly older mean age (57.8 vs. 42.6 years, <jats:italic>p<\/jats:italic> &amp;lt; 0.001), larger tumor size (3.1 cm vs. 2.0 cm, <jats:italic>p<\/jats:italic> = 0.003), a higher incidence of aggressive pathological subtypes (43.8% vs. 7.9%, <jats:italic>p<\/jats:italic> &amp;lt; 0.001), and an increased occurrence of distant metastasis (34.4% vs. 7.9%, <jats:italic>p<\/jats:italic> = 0.001). Over a median follow-up period of 32.5 months, this high-risk group demonstrated an elevated risk of local recurrence (32.1% vs. 9.5%, HR: 3.18, 95% CI: 1.15-8.78) and metachronous distant metastasis (38.1% vs. 2.9%, HR: 12.54, 95% CI: 2.60-60.41). Multivariate COX regression analysis confirmed that molecular characterize groups (HR: 5.77, 95% CI: 2.18-15.23, <jats:italic>p<\/jats:italic> &amp;lt; 0.001) and tumor size (HR: 1.32, 95% CI: 1.00-1.74, <jats:italic>p<\/jats:italic> = 0.047) independently predicted recurrence-free survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>ATA-RSS high-risk differentiated thyroid cancer often presents with late-hit genetic alterations, which are strongly associated with increased likelihood of structural recurrence. Molecular testing offers a precise approach to recurrence risk stratification in high-risk cases, enabling personalized follow-up and treatment strategies tailored to the specific prognostic profile.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1508404","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T05:21:42Z","timestamp":1737696102000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Molecular testing stratifies the risk of structural recurrence in high risk differentiated thyroid cancer: a retrospective cohort 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