Validation of molecular profiling to preoperatively predict aggressive pathologic features in differentiated thyroid cancer.

[BACKGROUND] The 2015 American Thyroid Association guidelines stratify recurrence risk of differentiated thyroid cancer using pathologic findings. Aggressive features may reclassify tumors as intermediate-to-high risk in patients initially suitable for lobectomy, warranting completion thyroidectomy. Signatures represent distinct patterns of mRNA expression on the basis of molecular pathway features. This study evaluated whether molecular expression profiles ("signatures") could preoperatively differentiate high-risk tumors and potentially guide extent of surgery.

[METHODS] Patients who underwent thyroid nodule molecular testing with the Afirma Genomic Sequencing Classifier and subsequent operative resection from 2017 to 2024 were identified. Using features described on surgical pathology, patients were grouped into ATA guideline-based low-risk or intermediate/high-risk cohorts. Among the signatures assessed, Invasion Score was developed to rule out extrathyroidal extension or extensive vascular invasion, whereas Sodium-Iodide Symporter Expression reflects mRNA production levels of the transmembrane glycoprotein involved in thyroid-iodine uptake. Signatures were compared among cohorts using Mann-Whitney U and Kruskal-Wallis tests. Logistic regression was used for multivariate analysis.

[RESULTS] Of 445 patients analyzed, 366 were low risk and 79 were intermediate/high risk. Among 30 signatures evaluated, expression varied significantly among study cohorts in 23 (77%). Multivariate analysis demonstrated the Invasion Score signature as predictive of greater American Thyroid Association risk classification (odds ratio, 1.3; 95% confidence interval, 1.1-1.5, P = .005) whereas Sodium-Iodide Symporter Expression was protective (odds ratio, 0.78; 95% confidence interval, 0.63-0.94, P = .015).

[CONCLUSION] Multiple signature expression profiles showed marked variation among American Thyroid Association risk classes and may help enhance preoperative prognostication. Although Invasion Score mirrors greater risk pathologic features, upregulated Sodium-Iodide Symporter Expression appears to protect from greater American Thyroid Association risk class, although further studies are needed to confirm.