504 chapter 13 added value of TIRADS in addition to these molecular imaging techniques [462, 742]. In our most recent study that compared [18F]FDG-PET/CT and MD and investigated its combined use, sequential application of both tests only appeared useful in case of a first-step negative MD result, to lower the risk of malignancy and ensure that active surveillance would be safe. In all other scenarios, the two diagnostics were complementary but the sequential use of the second test would not change the course of management as compared to the advised management based on the first test alone [725]. To the best of our knowledge, cost-effectiveness has never been investigated for any combination of diagnostic tests in indeterminate thyroid nodules. However, based on the univariate sensitivity analysis of our cost-utility study in [18F]FDG-PET/CT, cost-effectiveness may be anticipated. This univariate sensitivity analysis showed that the price of the [18F]FDG-PET/CT (may be read as “the test or combination of tests”) may range from €400 to €5,000 per patient (Table 4 and Figure 4, Chapter 6) and an [18F]FDG-PET/CT-driven workup would still amply be cost-effective [28]. This holds true under the assumption that a combination of diagnostics would only preserve or improve the diagnostic accuracy and thus the rate of beneficial treatments for benign as well as malignant nodules [725]. With an estimated price ranging from €750 to €1,000 for a partial-body [18F]FDG-PET/ CT, this would leave a sufficient €4,000 to €4,250 to finance a second (molecular) diagnostic. Considering the previous paragraphs of this discussion concerning clinical utility, cost-effectiveness, health care consumption volumes, and the selective use of resources, the sequential application of multiple diagnostics may be considered, but only provided that it changes the course of management and may change patient outcomes. Accurate patient selection, patient counselling, and multidisciplinary consultation are crucial to determine the most suitable course of management. Clinical relevance of missed thyroid malignancies As the terms ‘never’ and ‘always’ seem non-existent in medicine, using any kind of additional diagnostic test in indeterminate thyroid nodules, a small number of malignant nodules will initially be misdiagnosed as benign (i.e., false-negative test). Opportunely, the natural course of differentiated thyroid carcinoma is typically indolent [11, 743, 744]. When we consider the likely underlying biology when such a nodule would be [18F]FDG negative and/or MD negative, it is most likely that follow-up and a delayed diagnosis of these initially false-negative nodules will still result in timely diagnosis without relevant treatment delay and dismal prognostic consequences [25, 501, 744]. False-negativity in [18F]FDG-PET/CT In case of [18F]FDG-PET/CT, previously reported false-negative results have mostly concerned lowrisk carcinomas (i.e., TNM classification T1) [39, 40, 485]. Fewer unfavourable histopathological characteristics have been observed in [18F]FDG-negative thyroid carcinoma and [18F]FDG-uptake is
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