TERT promoter mutations in papillary thyroid carcinoma: association with gross extrathyroidal invasion and outcomes

Abstract Context Morbidity of papillary thyroid carcinoma (PTC) is primarily related to locoregional and distant metastases. Extrathyroidal extension (ETE) is associated with adverse outcomes; however, the biological heterogeneity across its degrees—particularly minimal (mETE) versus gross ETE (gETE)—remains incompletely characterized. While BRAFV600E and TERT promoter (TERTp) mutations have been linked to aggressive disease, their contributions to ETE severity are not fully established. Objective To compare clinical outcomes across different degrees of ETE and evaluate the association between molecular alterations and local aggressiveness in PTC. Methods A total of 352 PTCs (242 mETE; 81 gETE-T3; 29 gETE-T4) were evaluated for lymph node and distant metastases, disease recurrence/persistence, and response to therapy. BRAFV600E and TERTp (C228T/C250T) mutations were analyzed in 68 mETE and 28 gETE tumors and correlated with clinical outcomes. Results Increasing ETE severity was associated with progressively higher risks of lymph node and distant metastases, recurrence/persistence, and incomplete response to therapy (all p<0.001), independent of other risk factors. BRAFV600E prevalence did not differ between tumors with mETE (82.4%) and gETE (71.4%). In contrast, TERTp mutations were more frequent in gETE (46.4%) than mETE (16.2%; p=0.002) and were independently associated with gETE, distant metastases, and incomplete response to therapy. Conclusions Gross ETE is associated with progressively worse clinical outcomes, particularly in gETE-T4 tumors. While BRAFV600E does not distinguish microscopic from macroscopic invasion, TERTp mutations are associated with invasive local behavior, distant metastases, and incomplete response to therapy. These findings suggest that TERTp status may refine risk stratification in PTC with extrathyroidal extension.