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

Abstract

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 fine-needle 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, 0.630-0.953). 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 fine-needle aspiration, or surgical excision, even in the presence of a negative test.

Impact of the Italian Society of Anatomic Pathology and Diagnostic Cytology Classification of Thyroid Nodules in the Treatment of Indeterminate Follicular Lesions: Five-Year Results at a Single Center

“…On the other side, RAS mutation presented low sensitivity and low PPV (43.7% and 46.7%, respectively) with mediocre specificity and negative predictive values (NPV) (75.0% and 72.7%, respectively). is is once more in accordance with literature data [58] and can be easily explained considering that RAS mutation can often be present also in follicular adenomas [45][46][47][48].…”

Molecular Variants and Their Risks for Malignancy in Cytologically Indeterminate Thyroid Nodules

“…The data presented here suggest that variants in KRAS have a significantly lower PPV than variants in NRAS ( p = 0.002), and as more variant-specific PPV data on RAS become available, this may also hold true at the variant level. Differing cancer risks among specific variants may contribute to the heterogeneity reported for RAS performance across different studies (90,91). Thus, assigning a risk interpretation to a panel or group of genes/variants rather than to individual specific variants may be less accurate.…”

Circulating thyroid cancer biomarkers: Current limitations and future prospects

“…Results on RAS testing have been less encouraging. A meta‐analysis of 1025 patients with indeterminate nodules concluded that RAS mutational status is unlikely to alter clinical management due to low sensitivity …”