Heterogeneity in Positive Predictive Value of RAS Mutations in Cytologically Indeterminate Thyroid Nodules

Background: RAS mutations are common in the available mutational analysis of cytologically indeterminate (Cyto-I) thyroid nodules. However, their reported positive predictive value (PPV) for cancer is widely variable. The reason for this variability is unknown, and it causes clinical management uncertainty. A systematic review was performed, evaluating the PPV for cancer in RAS mutation positive Cyto-I nodules, and variables that might affect residual heterogeneity across the different studies were considered.

Methods: PubMed was searched through February 22, 2017, including studies that evaluated at least one type of RAS mutation in Cyto-I nodules, including any (or all) of the Bethesda III/IV/V categories or their equivalents and where the histological diagnosis was available. The PPV residual heterogeneity was investigated after accounting for Bethesda classification, blindedness of the histopathologist to the RAS mutational status, Bethesda category-specific cancer prevalence for each study, and which RAS genes and codons were tested. This was studied using five meta-regression models fit to different sets of Bethesda classification categories: Bethesda III, IV, or V (III/IV/V); Bethesda III or IV (III/IV); Bethesda III only; Bethesda IV only; and Bethesda V only.

Results: Of 1831 studies, 23 were eligible for data inclusion. Wide ranges of PPV were found at 0-100%, 28-100%, and 0-100% in Bethesda III, IV, and V, respectively. Residual heterogeneity remained moderately high for PPV after accounting for the above moderators for Bethesda III/IV/V (21 studies; I² = 59.5%) and Bethesda III/IV (19 studies; I² = 66.0%), with significant Cochran's Q-test for residual heterogeneity (p < 0.001). Among individual Bethesda categories, residual heterogeneity was: Bethesda III (eight studies; I² = 89.0%), IV (12 studies; I² = 53.5%), and V (10 studies; I² = 34.4%), with significant Cochran's Q-test for Bethesda III (p < 0.001) and IV (p = 0.04).

Conclusion: The PPV of RAS mutations in Bethesda III and IV categories is quite heterogeneous across different studies, creating low confidence in the accuracy of a single estimate of PPV. Clinicians must appreciate this wide variability when managing a RAS-mutated Cyto-I nodule. Future studies should seek to resolve this unexplained variability.