62 chapter 2 Combined and multistep diagnostics The previous chapters of this review addressed the large number of available diagnostic tools to assess indeterminate thyroid nodules. Most studies focused on a single diagnostic technique only. The elimination of between-study population-level differences is a major advantage when comparing the performance of multiple diagnostics independently in one study, optimally in a prospective, independent and blinded fashion. Moreover, assessment of multiple techniques in one study allows investigation of the complementary value of multiple techniques as a diagnostic tool by means of simultaneous or sequential testing while at the same time aiding to further unravel tumour biology as a research tool, especially in the current multidisciplinary in-hospital working environment. For example, the question how the presence of a certain oncogenic mutation relates to the (positive) result of an [18F]FDG-PET scan could be addressed. Piccardo et al. compared [99mTc]Tc-MIBI, [18F]FDG-PET/CT and US plus USE in 87 indeterminate TIR3 nodules with a 21% malignancy rate. [18F]FDG-PET/CT was the superior technique with 94% sensitivity and 58% specificity. Following a non-specific positive [18F]FDG-PET result, review of ultrasound characteristics offered slight further differentiation; it improved specificity to 77%. However, an additional negative [99mTc]Tc-MIBI scan increased specificity to 94%; this combination was found in 13% of patients [58]. Giovanella et al. performed both [99mTc]Tc-MIBI and a 7-gene mutation panel in cold indeterminate thyroid nodules. Combined testing did not improve diagnostic accuracy. Performance of the gene mutation panel was inferior to [99mTc]Tc-MIBI imaging. Of the seven (11%) mutation-positive nodules (four RAS mutations and three PAX8/PPARy rearrangements), only four were malignant. It is unclear whether the low sensitivity of the gene mutation panel in this study can be explained by the selected population of hypofunctioning nodules [108]. Elastosonography and ultrasonography USE is superior to ultrasound in indeterminate thyroid nodules – both individual US characteristics as well as combined US patterns described in various articles [248, 251, 253, 255, 257, 259, 260]. Two recent prospective studies demonstrated that additional USE evidently improved the diagnostic accuracy of US. Garino et al. included nodule stiffness as additional characteristic into a panel of US characteristics and demonstrated that USE identified eight additional malignancies that would have been missed by US assessment alone. Presence of one or more suspicious US/USE features was 100% sensitive; two or more 88% sensitive and 77% specific. Benign test results were found in 57% of patients. The authors suggested that the 6.4% remaining risk of malignancy– similar to the benign cytology category – would justify follow-up instead of diagnostic hemithyroidectomy in this group [248]. In another study of 315 Thy3 nodules, semi-quantitative USE correctly diagnosed
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