Disease site as an independent predictor of survival in radioiodine-refractory thyroid cancer.

Background: Differentiated advanced thyroid carcinoma (DATC) is rare, accounting for ~5% of thyroid tumors, including radioiodine-refractory thyroid tumors (RAI-R-TC) and thyroid tumors not amenable to thyroidectomy. Prognosis is poor, with a 10-year survival of ~10% and median life expectancy of 3-5 years. Systemic therapies are often required, but management remains challenging due to comorbidities and treatment-related toxicity. In particular, it is unknown whether outcomes differ between patients with predominantly locoregional disease and those with distant metastases. Patients and methods: We retrospectively analyzed a consecutive series of 43 patients with RAI-R-TC treated with tyrosine kinase inhibitors (TKIs). Patients were stratified according to the predominant site of disease involvement at TKI initiation: (i) locoregional progression with involvement of critical cervical structures, and (ii) progressive distant metastatic disease. Tumor response and disease progression were defined according to RECIST 1.1 criteria. Disease-specific survival (DSS) was estimated using the Kaplan-Meier method, and differences between the two groups were assessed using the log-rank test. Results: Median age at diagnosis was 63.3 years; 51.2% patients were females. Histology included papillary (n=26), follicular (n=10), poorly differentiated (n=6), and papillary-follicular (n=1). At presentation or shortly after, 44.2% patients had distant metastases; 55.8% had locally advanced disease, of whom 91.7% also developed distant spread. Patients with locoregional disease demonstrated significantly worse disease-specific survival compared with those presenting with distant metastases (p < 0.05). At last follow-up, 51.2% were stable, 11.6% progressed, 62.8% were alive, and 37.2% had died of disease. The difference in survival between the two groups was statistically significant. Conclusion: Despite belonging to the same disease entity, our preliminary data suggest that DATC patients show divergent prognostic outcomes depending on disease extent. Locoregional invasion appears to carry a particularly poor outcome, underscoring the need for differentiated and personalized therapeutic strategies. TKIs remain effective in both settings, but tailored management is warranted to address the distinct challenges of locoregional versus distant metastatic disease.