67 Diagnostic utility of molecular and imaging biomarkers 2 Discussion This review provides a comprehensive overview of the available literature on molecular and imaging biomarkers as additional diagnostics for thyroid nodules with indeterminate cytology (Bethesda III and IV) and their application in a clinical preoperative setting. Clinical utility requires more from a diagnostic than mere well-validated test performance and high rule-in or rule-out capacity. The 2015 ATA guidelines suggested that the ideal rule-out diagnostic for thyroid carcinoma should have a NPV similar to a benign cytological diagnosis (~96.3%) and the ideal rule-in test a PPV that is at least similar to a malignant cytological diagnosis (~98.6%) [17, 49]. The balance between test sensitivity and specificity – and their prevalence-dependent derivatives PPV and NPV – directly reflects on feasibility and cost-effectiveness estimates. A diagnostic with (near) perfect sensitivity but limited specificity is inefficient and unlikely cost-effective: the NPV will be close to 100%, but the majority of nodules will test positive. Therefore, instead of focusing on the reproducible highest sensitivity or specificity, a diagnostic is better appreciated by end points such as desired minimal rates of accurately prevented unbeneficial surgeries or accurately diagnosed carcinomas. More importantly, clinical utility demands that implementation of the ancillary test leads to changes in patient management and overall health benefits [30]. All these requirements directly depend on a plurality of epidemiological and economic factors within the tested population, such as the local test availability, professional expertise and case mix – prevalence of malignancy as well as the balance of various subtypes of indeterminate cytology including especially Hürthle-cell neoplasms and BRAF-mutation. Additionally, clinical utility considerations should include less tangible factors such as physician and patient preference, multidisciplinary decision making and compatibility with everyday clinical routine and logistics in endocrine practice. All things considered, global perspectives regarding the preferred diagnostic for indeterminate thyroid nodules likely greatly differ. Recommendation for clinical use of rule-out tests The most accurate currently available rule-out tests are the Afirma® GEC and [18F]FDG-PET(/CT) imaging. The Afirma® GEC had strikingly high sensitivity in nearly all studies [165, 167, 169-172]. However, there are concerns regarding the lack of strong validation studies. With a high degree of missing histology, especially in GEC negative nodules, there is a potentially strong diminution of the tests’ sensitivity if unresected GEC-negative lesions were less often benign than presumed. In the USA, physicians should locally validate the tests’ utility prior to implementation. However, with its limited global availability, high costs and low probability of cost-effectiveness, clinical implementation of the Afirma® GEC outside the USA is currently not favoured [53, 159, 175-178]. FDG-PET/CT may be the preferred rule-out test for indeterminate thyroid nodules in a European
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