Second Primary Malignancies Among Pediatric and Young Adult Survivors of Differentiated Thyroid Cancer: Real-World Evidence

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Background: Differentiated thyroid cancer (DTC) is the most common endocrine malignancy among children, adolescents, and young adults (CAYA). While prognosis is generally favorable, rising incidence, longer survivorship, and radioactive iodine (RAI) treatment raise concern for late effects, particularly second primary malignancies (SPMs) and late mortality. Objective: To evaluate SPM risk, all-cause mortality, and the impact of RAI in CAYA DTC survivors. Methods: Retrospective cohort study (1982–2022) using Clalit Health Services records, including DTC patients diagnosed <40 years, who survived ≥2 years. Participants were matched to cancer-free controls (1:4) by birth year, sex, ethnicity, and socioeconomic status. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Among 5267 DTC survivors ( n = 497 [∼9.5%] diagnosed before age 20 years) and 21,062 matched controls, SPM incidence was higher in survivors with 50% increased risk (500 vs. 360 per 100,000 person-years; HR 1.50, CI 1.34–1.67) and occurred after a shorter latency (13.8 vs. 15.1 years; p = 0.042). Survivors diagnosed before age 20 were significantly younger at data retrieval than those diagnosed at 20–40 years (median 33 vs. 47 years; p < 0.001) and had significantly lower SPM rates ( n = 28 [5.6%] vs. n = 398 [9.0%]; p = 0.012). Compared with RAI-untreated survivors, SPM risk increased after one RAI treatment (HR 1.91, CI 1.52–2.40) and further after ≥2 RAI treatments (HR 2.73, CI 2.13–3.50). Overall mortality rate was low ( n = 148, 2.8%) and similar to that of matched controls ( n = 517, 2.5%) but was significantly higher among survivors who developed SPMs and/or received RAI treatment ( p < 0.001). Conclusions: Over four decades of follow-up, SPMs were identified as a significant long-term risk among CAYA DTC survivors, frequently manifesting many years after the initial diagnosis. Both SPM occurrence and higher cumulative RAI doses were associated with increased mortality. These findings support careful risk-adapted use of RAI and underscore the need for extended surveillance, particularly for those diagnosed in childhood or adolescence, as malignancies may arise many years after diagnosis.

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