Outcomes of TSHR mutations in indeterminate thyroid nodules

BACKGROUND: The thyrotropin receptor (TSHR) mutation can be present in autonomously functioning thyroid nodules (AFTNs). Our objective was to evaluate whether patients with a TSHR mutation developed AFTNs and to assess the impact of this mutation on thyroid malignancy. METHODS: We conducted a multicenter retrospective study of 1211 patients from Montreal, Canada, and from Tel Aviv, Israel, who underwent molecular testing (ThyroseqV3®) from January 2018 to December 2022 following an indeterminate cytology result (Bethesda III-IV). All TSHR-positive patients (n = 56) and 90 randomly selected mutation-negative patients were included. TSH levels were measured at least twice over 1-3 years following molecular testing. RESULTS: The case group was predominantly female (94.8%) with a mean age of 51.2 years. The mean TSH levels in the control and case groups were 2.29 (CI=95% 1.93-2.66) and 1.55 (CI=95% 1.23-1.86) at first follow-up, and 2.17 (CI=95% 1.80-2.54) and 1.33 (CI=95% 1.01-1.66) at second follow-up. Higher allele frequency correlated with lower TSH levels (P = 0.005, P = 0.002). All isolated TSHR mutations were associated with benignity regardless of allele frequency, while co-occurring genetic alterations were associated with malignant outcomes. CONCLUSIONS: TSHR mutations are generally benign and correlate with lower TSH levels. Co-mutations may influence thyroid function and malignancy risk.