General discussion 503 13 consider the therapeutic consequences and/or effect on patient outcomes following a positive test result. Following de-escalation of the surgical treatment of low-to-intermediate risk papillary and follicular thyroid carcinomas <4 cm [17], the therapeutic consequences of a positive pre-operative test result are likely confined, as it may infrequently necessitate immediate total thyroidectomy in Bethesda III/IV thyroid nodules <4 cm, which infrequently carry prognostically high-risk mutations (Chapter 12) [698, 725]. Consequently, in a patient with a Bethesda III/IV nodule <4 cm, a desire for surgery, and no other risk factors (i.e., unifocal/unilateral disease, no suspicion of extrathyroidal extension or lymph node metastases, no history of irradiation to the head and neck, and no family history of differentiated thyroid cancer), diagnostic thyroid lobectomy may be performed without preoperative MD [17]. If desired for further risk stratification, MD could subsequently be performed on histopathology specimens of malignant, borderline, or difficult-to-diagnose cases. MD on histopathology has the added benefit that it most likely results in fewer nondiagnostic MD results due to a higher DNA/RNA content than the yield from cytology smears [705, 725]. In approximately half of the patients undergoing initial thyroid lobectomy for differentiated thyroid carcinoma, additional completion thyroidectomy is advised due to unfavourable histopathological features [735-737]. The presence of BRAF-like but not RAS-like mutations is associated with unfavourable histopathological characteristics, including extra-thyroidal extension and lymph node metastases [738-740]. Since surgical de-escalation was incorporated in the ATA guidelines, the number of initial total thyroidectomies decreased and the number of thyroid lobectomies and completion thyroidectomies increased, with unknown consequences for cost-effectiveness [737]. The horn of plenty: combining additional diagnostics In our 2018 systematic review, we advocated that the diagnostic possibilities are endless and that a multimodality stepwise approach likely offers the most accurate diagnosis for indeterminate thyroid nodules by sequentially applying one sensitive rule-out test and one specific rule-in test [25]. Here, I would like to re-evaluate that point of view. At the time of our review, the combined or sequential use of multiple diagnostics, especially diagnostics from different fields of expertise (i.e., combining MD and imaging) had infrequently been studied [58, 351]. Since then, little new evidence has appeared. A small number of studies investigated the added diagnostic value of assessing ultrasound characteristics (primarily nodule size, but also TIRADS and ATA ultrasound classification systems) in combination with MD [484, 698, 720, 741]. A single study by Piccardo et al. showed that [18F]FDG-PET/CT, TIRADS and the cytological classification are all independent predictors for malignancy [40]. Schenke et al. and Trimboli et al. only included EU-TIRADS classification IV and V nodules in their [99mTc]Tc-methoxyisobutylisonitrile (MIBI) and [18F]FDG-PET/CT studies, respectively, complicating drawing conclusions regarding the
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