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The management for totally thyroidectomized differentiated thyroid cancer (TT-DTC) patients with unexplained hyperthyroglobulinemia remains indeterminate because of evidence scarcity. This multicenter study aimed at prospectively evaluating the response to radioiodine ( 131 I) adjuvant therapy (RAT) and its potential role in risk stratification and causal clarification. Methods: TT-DTC patients with stimulated serum thyroglobulin levels greater than 10 ng/mL but no structurally evident disease were consecutively enrolled in 5 tertiary-care institutions. After the administration of 5.55 GBq of 131 I, the risk of persistent, recurrent, or metastatic differentiated thyroid cancer (prmDTC) was compared with that before RAT. The causes of hyperthyroglobulinemia were explored-and the response to RAT assessed-6-12 mo after RAT. The change in suppressed thyroglobulin level was reported. Results: A cohort of 254 subjects with a median stimulated thyroglobulin level of 27.1 ng/mL was enrolled for the analyses. Immediately after RAT, low, intermediate, and high risk were identified in 5.9%, 88.6%, and 5.5% patients, respectively, with no significant difference in risk stratification compared with that before RAT ( P = 0.952). During the follow-up (median, 10.6 mo), hyperthyroglobulinemia was ultimately attributed to a thyroid remnant, biochemical disease, and structural or functional disease in 17.3%, 54.3%, and 28.4% of subjects, respectively. In addition, responses that were excellent, indeterminate, biochemically incomplete, and structurally or functionally incomplete were achieved in 18.1%, 27.2%, 36.2%, and 18.5% of patients, respectively. Notably, the distribution for either cause of hyperthyroglobulinemia or response to RAT was comparable among the 3 postoperative risk groups. Suppressed thyroglobulin levels in patients who merely received RAT declined significantly over time. Conclusion: Our study demonstrated that over 90% of TT-DTC patients with unexplained hyperthyroglobulinemia are stratified as being at intermediate to high risk, and RAT using 5.55 GBq of 131 I reveals biochemical, functional, or structural disease and yields a non-structurally or -functionally incomplete response in more than 80% patients, suggesting that TT-DTC patients with unexplained hyperthyroglobulinemia are explicit candidates for RAT.

the journal of nuclear medicine

Unexplained Hyperthyroglobulinemia in Differentiated Thyroid Cancer Patients as an Indication for Radioiodine Adjuvant Therapy: A Prospective Multicenter Study