The utility of combined mutation analysis and microRNA classification in reclassifying cancer risk of cytologically indeterminate thyroid nodules

• Published in: Diagnostic cytopathology Vol. 47; no. 4; pp. 268 - 274
• Main Authors: Banizs, Anna B., Silverman, Jan F.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.04.2019; Wiley Subscription Services, Inc
• Subjects: Biomarkers, Tumor - genetics; Biomarkers, Tumor - standards; Cellular biology; Class I Phosphatidylinositol 3-Kinases - genetics; Classification; Cytology; Health risk assessment; Health risks; Humans; Malignancy; microRNA classification; MicroRNAs; MicroRNAs - classification; MicroRNAs - genetics; miRNA; Mutation; mutation analysis; Nodules; Pax8 protein; PAX8 Transcription Factor - genetics; Predictive Value of Tests; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins c-ret - genetics; Risk assessment; risk reclassification; Thyroid; Thyroid cancer; Thyroid gland; Thyroid Nodule - classification; Thyroid Nodule - genetics; Thyroid Nodule - pathology; thyroid nodules; Tumors; microRNA classification; thyroid cancer; thyroid nodules; mutation analysis; risk reclassification
• ISSN: 8755-1039; 1097-0339
• DOI: 10.1002/dc.24087

Objectives Real‐world clinical results of (1) Bethesda categorization, (2) mutation analysis, and (3) a microRNA classifier were correlated to show the utility of molecular analysis in assessing malignancy risk of indeterminate thyroid nodules. Methods Cytology and molecular results of clinically tested thyroid nodules were compared. An additional microRNA threshold was determined based on nodules with known disease status, establishing a 3‐tiered microRNA approach to clinical risk assessments. Expected rate of malignancy given mutation panel and 3‐tiered microRNA approach was validated in an independent cohort of atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) and follicular neoplasm or suspicious for follicular neoplasm (FN/SFN) nodules with surgically derived outcomes. Results In 2685 patients clinically tested, PIK3CA, PAX8/PPARγ, and RET/PTC mutations occurred in less than 1%. Of note, 2% had BRAFV600E mutation and 82% lacked mutations. The maximum expected risk of malignancy in nodules lacking mutations was 9% and 17% for AUS/FLUS and FN/SFN nodules, respectively. Positive microRNA status further increased risk, with the most worrisome status (level‐3) elevating risk to 36% and 54%, respectively. RAS mutations occurred in 15% of nodules tested clinically, including in 8% of those that were cytologically benign. The maximum expected risk of malignancy in nodules with RAS or PAX8/PPARγ mutations was 49% and 65% for AUS/FLUS and FN/SFN nodules, respectively. Positive microRNA status further increased risk, with the most worrisome microRNA status (level‐3) elevating risk to 85% and 91%, respectively. Conclusions Mutation panels alone do not sufficiently risk stratify thyroid nodular disease. microRNA classification complements cytology and mutation analysis with the capacity to better differentiate nodules at high risk of malignancy.