Late-onset distant metastases confer poor prognosis in patients with well-differentiated thyroid cancer

Background: Distant metastases from well-differentiated thyroid carcinoma (WDTC) occasionally occur over a wide range of time intervals after primary thyroid surgery. The prognostic impact of the timing of distant metastasis onset remains unclear. Methods: We retrospectively reviewed the clinicopathologic features and clinical outcomes of 57 patients with WDTC and distant metastases, and evaluated the mutational profiles of BRAF, RAS, and TERT promoter genes. All patients underwent thyroidectomy and radioactive iodine (RAI) ablation using the same treatment protocol. Synchronous distant metastases were defined as those detected within 12 months of the primary WDTC diagnosis. Metachronous metastases were considered early- and late-onset diseases if detected 1-5 and ?5 years after the primary diagnosis, respectively. Results: In all patients, the 5- and 10-year cancer-specific survival (CSS) rates after the diagnosis of distant metastasis were 86% and 57%, respectively. Late-onset (>= 5 years) metachronous distant metastasis was associated with age of >= 55 years (P=0.043) and patients refractory to RAI therapy (P=0.026). TERT promoter mutations were associated with RAI refractivity (P=0.026). BRAF V600E and RAS mutations had no prognostic significance. Bone metastasis (P=0.002) and the onset time of distant metastasis (P=0.004) were associated with poor CSS. There was no significant difference in CSS between patients with synchronous distant metastases and those with early-onset (1-5 years) metachronous distant metastases. In the multivariate analysis, bone metastasis [hazard ratio (HR) =10.24; 95% confidence interval (CI): 1.25-83.74; P=0.030] and late-onset (>= 5 years) metachronous distant metastasis (HR =5.20; 95% CI: 1.01-26.63; P=0.048) were independent predictors for worse CSS. Conclusions: The prognosis of patients with WDTC was poorer for late metachronously detected metastases than for synchronous or early metachronous metastases. Patients with distant metastasis occurring 5 years later after primary thyroid diagnosis should, therefore, be more carefully treated.