Harnessing Molecular Diagnostics in Cytologically-Indeterminate Thyroid Nodules

Samantha Peiling YangSingapore Speaker Harnessing Molecular Diagnostics in Cytologically-Indeterminate Thyroid NodulesCytologically indeterminate thyroid nodules (Bethesda III–IV) remain a common diagnostic challenge, as cytology alone cannot reliably distinguish benign from malignant disease. Molecular diagnostic tests have emerged as important adjuncts to refine malignancy risk and guide clinical management. This presentation reviews the molecular landscape of thyroid cancer relevant to indeterminate nodules, including key somatic alterations such as BRAF, RAS, and gene fusions (e.g., RET, NTRK, ALK), and discusses the performance of contemporary molecular diagnostic tests. Data from North America and emerging real-world experience in Singapore will be highlighted. The clinical utility of molecular diagnostics in reducing unnecessary diagnostic surgery and informing the extent of surgical management will be discussed, together with current guidance from the ATA 2025 guidelines on integrating molecular results with clinical, radiologic, and cytopathologic findings. Re-Differentiation Therapy in RAI-Refractory Thyroid CancerRadioactive iodine (RAI) therapy remains a cornerstone in the management of differentiated thyroid cancer. However, a subset of patients develop RAI-refractory disease due to loss of iodine-handling gene expression, including the sodium–iodide symporter (NIS). This loss is frequently associated with activation of the MAPK signalling pathway driven by oncogenic alterations such as BRAF and RAS mutations. While systemic therapy with multi-targeted or mutation-specific tyrosine kinase inhibitors (TKIs) can control disease progression, these treatments are generally not curative and do not consistently restore RAI sensitivity. Re-differentiation therapy has emerged as a promising strategy to restore iodine uptake by targeting MAPK signalling and re-inducing thyroid-specific gene expression. This presentation will review the biological rationale for re-differentiation therapy and summarize key clinical studies evaluating BRAF and MEK inhibition in patients with RAI-refractory thyroid cancer. Emerging approaches, optimal treatment duration, and potential predictors of response will also be discussed, highlighting the potential of re-differentiation therapy to restore the therapeutic benefit of RAI in selected patients.