Introduction Thyroid nodules with indeterminate cytology (Bethesda III and IV) present a diagnostic challenge, as conventional cytology offers limited predictive value and can lead to unnecessary surgeries. Recently, validated molecular classifiers have been developed with the aim of improving the stratification of the risk of malignancy in these nodules and optimizing clinical decision-making. Objectives To evaluate and compare the diagnostic yield of validated commercial molecular systems, including ThyroSeq and Afirma, versus conventional cytology in Bethesda III and IV thyroid nodules, using the result of postsurgical histopathology as a reference.

Method A structured review of prospective studies, randomized controlled trials, retrospective cohorts, and meta-analyses that analyzed the performance of commercial molecular classifiers in Bethesda III and IV nodules was conducted. We included studies that reported sensitivity, specificity, positive and negative predictive value, and that used postoperative histopathology as a reference standard. The sample volume of individual studies ranges from several hundred to more than six thousand nodules using pooled analyses.

Results The selected studies show that molecular classifiers such as ThyroSeq v3 and Afirma GSC achieve a high sensitivity and negative predictive value (≥94% and ≥96%, respectively), outperforming conventional cytology. Specificity and positive predictive value show greater variability between studies and clinical settings. The use of these classifiers has made it possible to reduce the number of unnecessary surgeries on benign nodules.

Conclusions The available evidence supports that validated molecular classifiers increase diagnostic accuracy in thyroid nodules with indeterminate cytology, reduce unnecessary surgical interventions, and improve clinical decision-making compared to conventional cytology, using histopathology as a standard reference.

The authors have declared no competing interest.

This study did not receive any funding

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