485 MD and [18F]FDG-PET/CT: complementing techniques or waste of valuable resources? 12 Discussion To the best of our knowledge, the current study was the first to compare the preoperative performance of MD and [18F]FDG-PET/CT in a prospective cohort of ITN. According to the ATA guidelines, an ideal rule-out or rule-in test would have the NPV of a benign (Bethesda II, 96.3%) or PPV of a malignant (Bethesda VI, 98.6%) cytological diagnosis, respectively [17]. Although MD and [18F]FDG-PET/CT are both accurate rule-out tests, the reported 97% NPV of a double negative test in non-oncocytic nodules and the 95% NPV of [18F]FDG-PET/CT come closest to this recommendation. With 63% concordance between tests, MD and [18F]FDG-PET/CT are complementary and their combined use may allow for a more accurate differentiation between benign and malignant nodules. However, when acknowledging management consequences, the benefits of sequential testing may be more confined. A schematic representation of a stepwise approach in non-oncocytic nodules that starts with either MD or [18F]FDG-PET/CT (Figures 3 and 4) illustrates that an additional [18F]FDG-PET/CT scan may be beneficial following a negative first-step MD result to further reduce the rate of malignancy and ensure that withholding diagnostic thyroid surgery is oncologically safe. Following a positive MD result, diagnostic hemithyroidectomy would be advised regardless of the result of an additional [18F]FDG-PET/CT, and an [18F]FDG-PET/CT as a second-step additional diagnostic should not be recommended in that case. When [18F]FDG-PET/CT is used as the primary diagnostic, the latter also applies to performing MD as a second step following a positive [18F]FDGPET/CT scan. Following a first-step, negative [18F]FDG-PET/CT no additional MD is required either: not only may its 94% NPV in non-oncocytic nodules suffice to refrain from diagnostic surgery, the additional yield of second-step MD may be limited, too, as 81% of [18F]FDG negative nodules are also MD negative [501]. Based on the current study and in line with other literature, MD including CNA-analysis could be considered in the pre-operative workup of oncocytic ITN, in particular if larger validation studies can confirm these results [484, 695]. Dependent on the diagnostic rate of MD in cytology (Figures 3 and 4), MD including CNA-LOH analysis may accurately rule-out malignancy in oncocytic nodules. Visual assessment of [18F]FDG-PET/CT is unable to differentiate between benign and malignant oncocytic nodules, with a BCR of merely 3% that is likely related to the abundance of mitochondria in oncocytic cells [480, 501, 503]. Visual [18F]FDG-PET/CT assessment is therefore never advised in oncocytic nodules, and it is therefore not incorporated in Figure 3. Quantitative [18F]FDG-PET/CT assessment methods that include the crucial distinction between oncocytic and non-oncocytic nodules are still under investigation. Two previous studies found that a
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