Diagnostic Value of RAS Mutations in Indeterminate Thyroid Nodules: Systematic Review and Meta-analysis

Objectives. To determine the diagnostic value of HRAS, KRAS, and NRAS mutations in fine-needle aspiration biopsies of thyroid nodules that are nondiagnostic on cytology. Data Sources. PubMed, Scopus, Embase, CINAHL. Review Methods. Two authors independently searched the data sources. To be included, studies reported the RAS mutational status and postoperative histopathologic diagnosis of nodules that exhibited indeterminate cytology after fineneedle aspiration biopsy. Data were extracted to calculate sensitivity, specificity, and positive/negative predictive values of any HRAS, KRAS, or NRAS mutation. A meta-analysis was performed to generate pooled values for each parameter. Results. A total of 7 studies with a combined 1025 patients met inclusion criteria. The pooled sensitivity of a RAS mutation for detecting cancer was 0.343 (95% confidence interval [ 95% CI], 0.198-0.506), while the pooled specificity was 0.935 (95% CI, 0.882-0.973). The weighted averages for positive predictive value and negative predictive value were 78.0% and 64.0%, respectively, with 68.0% accuracy. The positive likelihood ratio was 4.235 (95% CI, 1.506-11.910), and the negative likelihood ratio was 0.775 (95% CI, 0.6300.953). Conclusion. Our data suggest that testing for any RAS mutation is unlikely to change the clinical management of thyroid nodules that have indeterminate cytology. While a RAS mutation may rule in malignancy, the sensitivity of testing is low enough to merit further mutational analysis, repeat fineneedle aspiration, or surgical excision, even in the presence of a negative test.