1 Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University and Arthur G. James Cancer Center, Columbus, Ohio.
2 Center for Biostatistics, Division of Human Genetics, The Ohio State University and Arthur G. James Cancer Center, Columbus, Ohio.
Thyroid. 2018 Jun;28(6):729-738. doi: 10.1089/thy.2017.0635. Epub 2018 May 16.
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.
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.
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; I = 59.5%) and Bethesda III/IV (19 studies; I = 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; I = 89.0%), IV (12 studies; I = 53.5%), and V (10 studies; I = 34.4%), with significant Cochran's Q-test for Bethesda III (p < 0.001) and IV (p = 0.04).
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.
RAS 突变在细胞学不确定（Cyto-I）甲状腺结节的可获得突变分析中很常见。然而，其报告的癌症阳性预测值（PPV）差异很大。造成这种差异的原因尚不清楚，这导致了临床管理的不确定性。我们进行了一项系统评价，评估了 RAS 突变阳性的 Cyto-I 结节中癌症的 PPV，并考虑了可能影响不同研究之间剩余异质性的变量。
通过 2017 年 2 月 22 日检索 PubMed，包括评估 Cyto-I 结节中至少一种 RAS 突变的研究，包括任何（或所有）Bethesda III/IV/V 类别或其等同类别，并且可获得组织学诊断。在考虑到 Bethesda 分类、组织病理学家对 RAS 突变状态的盲法、每个研究的特定 Bethesda 类别癌症患病率以及测试了哪些 RAS 基因和密码子后，调查了 PPV 的剩余异质性。使用五个元回归模型对不同的 Bethesda 分类类别进行拟合来研究这一点：Bethesda III、IV 或 V（III/IV/V）；Bethesda III 或 IV（III/IV）；Bethesda III 仅；Bethesda IV 仅；和 Bethesda V 仅。
在 1831 项研究中，有 23 项符合数据纳入标准。Bethesda III、IV 和 V 的 PPV 范围分别为 0-100%、28-100%和 0-100%。在考虑了上述调节因素后，Bethesda III/IV/V（21 项研究；I=59.5%）和 Bethesda III/IV（19 项研究；I=66.0%）的 PPV 仍存在中度高度的剩余异质性，Cochran's Q 检验有显著差异（p<0.001）。在各个 Bethesda 类别中，剩余异质性为：Bethesda III（八项研究；I=89.0%）、IV（十二项研究；I=53.5%）和 V（十项研究；I=34.4%），Bethesda III 的 Cochran's Q 检验有显著差异（p<0.001）和 IV（p=0.04）。
Bethesda III 和 IV 类别的 RAS 突变在不同研究之间的 PPV 差异很大，这使得对单个 PPV 估计的准确性缺乏信心。临床医生在管理 RAS 突变的 Cyto-I 结节时必须认识到这种广泛的变异性。未来的研究应努力解决这种无法解释的变异性。
