Molecular Testing in Thyroid Nodules: How Much Does It Change Clinical Practice?

Background/Objectives: Molecular testing is most commonly performed in evaluation of thyroid nodules with indeterminate Fine Needle Aspiration Biopsy (FNAB) results. However, in clinical practice, thyroidectomy may still be pursued in patients who present with clear clinical indications despite a benign molecular test result. The aim of this study is to identify clinical factors that influence the decision to proceed with surgery in the presence of a benign molecular test result. Methods: Patients who were evaluated in the outpatient clinic for thyroid nodules at one institution between January 2016 and January 2024 were retrospectively reviewed. Patients with FNAB results corresponding to Bethesda categories III or IV and a benign result on the Afirma molecular test were included. Demographic data, medical and family history, characteristics of thyroid nodules (including ultrasonographic features), surgical history, and postoperative pathology results were analyzed. Patients were divided into two groups based on clinical management-Observation (Group-1) or Thyroidectomy (Group-2)-and compared using Chi-square tests for bivariate analysis and multivariable logistic regression. Results: A total of 177 patients were included, with 87 (49.1%) in the observation group and 90 (50.9%) in the surgical group. Mean age was 55.9 ± 13.9 years and median nodule size (IQR) was 2.8 cm (1.95-4.0 cm). Bivariate analysis revealed the surgical group had significantly higher proportions of patients with compressive symptoms (p < 0.001), hyperthyroidism (p = 0.01), nodules >4 cm (p < 0.001) and documented nodule growth during follow-up (p < 0.001). Multivariate logistic regression identified the following factors as independently associated with the decision to proceed with surgery: compressive symptoms (OR: 23.2; 95%CI: 6.06-88.89; p < 0.001), hyperthyroidism (OR: 5.87; 95%CI: 1.63-21.20; p = 0.007), nodule size >4 cm (OR: 11.36; 95%CI: 3.90-33.12; p < 0.001), and increasing nodule size during follow-up (OR: 7.85; 95%CI: 2.72-22.65; p < 0.001). Conclusions: Despite a benign molecular test result, patients exhibiting compressive symptoms, hyperthyroidism, nodules larger than 4 cm, or evidence of nodule growth during follow-up are significantly more likely to undergo thyroidectomy. In such cases, molecular testing may offer limited clinical utility and could be omitted to optimize cost-effectiveness.