Molecular Classification of Thyroid Nodules with Indeterminate Cytology: Development and Validation of a Highly Sensitive and Specific New miRNA-Based Classifier Test Using Fine-Needle Aspiration Smear Slides

Abstract

Background: Thyroid nodules can be identified in up to 68% of the population. Fine-needle aspiration (FNA) cytopathology classifies 20%–30% of nodules as indeterminate, and these are often referred for surgery due to the risk of malignancy. However, histological postsurgical reports indicate that up to 84% of cases are benign, highlighting a high rate of unnecessary surgeries. We sought to develop and validate a microRNA (miRNA)-based thyroid molecular classifier for precision endocrinology (mir-THYpe) with both high sensitivity and high specificity, to be performed on the FNA cytology smear slide with no additional FNA.Methods: The expression of 96 miRNA candidates from 39 benign/39 malignant thyroid samples, (indeterminate on FNA) was analyzed to develop and train the mir-THYpe algorithm. For validation, an independent set of 58 benign/37 malignant FNA smear slides (also classified as indeterminate) was used.Results: In the training set, with a 10-fold cross-validation using only 11 miRNAs, the mir-THYpe test reached 89.7% sensitivity, 92.3% specificity, 90.0% negative predictive value and 92.1% positive predictive value. In the FNA smear slide validation set, the mir-THYpe test reached 94.6% sensitivity, 81.0% specificity, 95.9% negative predictive value, and 76.1% positive predictive value. Bayes' theorem shows that the mir-THYpe test performs satisfactorily in a wide range of cancer prevalences.Conclusions: The presented data and comparison with other commercially available tests suggest that the mir-THYpe test can be considered for use in clinical practice to support a more informed clinical decision for patients with indeterminate thyroid nodules and potentially reduce the rates of unnecessary thyroid surgeries.

Preoperative metabolic classification of thyroid nodules using mass spectrometry imaging of fine-needle aspiration biopsies

“…lesion is malignant or benign and thus aid in the diagnosis and clinical management of patients with indeterminate thyroid FNAs (8)(9)(10)(11)(12)(13). The original Afirma gene expression classifier (GEC), for example, measures the expression of 167 genes in an FNA sample to predict whether the nodule is either benign or suspicious with a sensitivity of 90% and a specificity of 52% when predicting on a set of 265 FNAs with indeterminate cytology (8).…”

Multi-omics Signatures and Translational Potential to Improve Thyroid Cancer Patient Outcome

“…In the training set, the miR-THYpre test reached 89.7% sensitivity, 92.3% specificity, 90% negative predictive value and 92.1% positive predictive value. In the validation cohort, the miR-THYpre reached 94.6% sensitivity, 81% specificity, 95.9% negative predictive value, and 76.1% positive predictive value [182].…”

Molecular tests for surgery indication in thyroid nodules: Should Bethesda V cytology be included?

“…2 Similarly, the sensitivity and specificity of the mir-THYpe are 94% and 81%, respectively. 3 In B-V nodules, the mir-THYpe was positive in 94% of the post-surgery samples and in 97% of the cytological samples of malignant tumors, while the test was negative in all benign samples. 3 When noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is excluded, the estimated ROM for B-V nodules drops to 50% to 75% according to table 1 of the review of Considering the performance of molecular tests mentioned earlier 2,3 and applying these tests in a context in which even B-V nodules would have a ROM of approximately 40% (TI-RADS 3 or low suspicion), a NPV of 94% would be obtained, which is sufficient to rule out the need for immediate surgery and to safely choose patient monitoring.…”

“…3 In B-V nodules, the mir-THYpe was positive in 94% of the post-surgery samples and in 97% of the cytological samples of malignant tumors, while the test was negative in all benign samples. 3 When noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is excluded, the estimated ROM for B-V nodules drops to 50% to 75% according to table 1 of the review of Considering the performance of molecular tests mentioned earlier 2,3 and applying these tests in a context in which even B-V nodules would have a ROM of approximately 40% (TI-RADS 3 or low suspicion), a NPV of 94% would be obtained, which is sufficient to rule out the need for immediate surgery and to safely choose patient monitoring. 5 In conclusion, our hypothesis is that molecular tests might be useful to define the indication for surgery also in B-V nodules given that the patients are not high risk for thyroid malignancy, the nodule exhibits a low suspicion sonographic pattern for malignancy (or TI-RADS 3), and that molecular tests with very good performance (sensitivity ≥92% and specificity >80%) 5 are used.…”