55 Diagnostic utility of molecular and imaging biomarkers 2 Functional and molecular imaging [99mTc]Tc-MIBI Hexakis(2-methoxy-2-methylpropylisonitrile)technetium[99mTc] ([99mTc]Tc-MIBI) is a Technetium-99mlabeled radiopharmaceutical, primarily known for its use in myocardial perfusion imaging since the 1980s and more recently the evaluation of hyperparathyroidism. Uptake of [99mTc]Tc-MIBI, a lipophilic cation, reflects both perfusion and the number of active mitochondria in the cells of the thyroid nodule and thus its oxidative burden [108, 293]. [99mTc]Tc-MIBI scintigraphy is more suitable for the differentiation between benign and malignant thyroid nodules than scintigraphy with 99mTc-pertechnetate (99mTcO4 -) or radioisotopes of iodide (often 131I-,123I- or 124I-). These latter tracers interrogate the sodium-iodide symporter of the thyrocyte and are frequently used to assess thyroid nodule functioning to distinguish autonomous (“hot”) from hypofunctioning (“cold”) nodules. They are neither specific nor effective to detect malignancy: benign nodules can be anything from hyper- to hypofunctioning, and far outnumber the carcinomas. Still, thyroid malignancies are almost always hypofunctioning: decrease of the sodium-iodide symporter or thyroid peroxidase are hallmarks of cell dedifferentiation and lead to loss of iodidetrapping function and thus 99mTc-pertechnetate or radioiodine uptake [17, 293-295]. [99mTc]TcMIBI uptake is independent of iodide trapping and organification in the thyrocytes. Nodules with increased uptake and late retention of [99mTc]Tc-MIBI are suspicious for malignancy [108, 293]. A 2013 meta-analysis by Treglia et al. demonstrated 82% sensitivity and 63% specificity for [99mTc]TcMIBI scintigraphy in clinically suspicious, hypofunctioning, cytologically unselected thyroid nodules. Hyperfunctioning benign adenomas can show false-positive increased uptake of [99mTc]Tc-MIBI due to their increased metabolic needs, thereby decreasing test specificity [293]. Only three studies investigated the role of [99mTc]Tc-MIBI in indeterminate thyroid nodules. In all studies, evaluation of thyroid nodules was performed by dual-time planar imaging: an early image was made ranging from 10-20 minutes after injection of the radiopharmaceutical and a delayed image 60-120 minutes post injection. The intensity of the [99mTc]Tc-MIBI uptake within the nodule, and possible increased uptake or denoting retention on delayed imaging were assessed and compared to the physiological washout of the tracer from normal thyroid tissue. A visual pattern of increased [99mTc]Tc-MIBI uptake on early images that persisted or further increased on the delayed images was generally considered suspicious for malignancy. The individual study sensitivity and specificity for this interpretation ranged from 56% to 79% and from 52% to 96%, respectively [58, 108, 296]. Despite the limited number of available studies, the performance of [99mTc]Tc-MIBI in indeterminate thyroid nodules seems insufficient and less accurate than in cytologically unselected nodules [293]. Nonetheless, Giovanella et al. demonstrated that NPV for this method could increase from 88%
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