60 chapter 2 Contrasting the generally strong sensitivity, specificity of [18F]FDG-PET is consistently poor. The underlying mechanism is not yet fully elucidated. The negative influence of Hürthle cell cytology may be partly responsible. It could also be explained by cellular atypia, which was significantly and independently related to [18F]FDG uptake, and found in both benign and malignant lesions. Atypia was also related to the presence of Hürthle cells [309]. Sebastianes et al. hypothesized that [18F]FDG uptake is related to variations in gene expression patterns. They suggested that genetic variations between populations may also explain the varying diagnostic accuracy of [18F]FDG-PET between studies [306]. In conclusion, [18F]FDG-PET(/CT) has the potential to accurately rule-out malignancy in all indeterminate nodules except Hürthle cell lesions. It could prevent unnecessary diagnostic surgery for a significant number of benign thyroid nodules. Sample sizes of existing studies are small, but larger prospective trials are currently ongoing to settle the diagnostic value of this technique and its utility in clinical practice. We recommend that these studies also focus on identifying (genetic) causes for the occasional false-negativity and generally low specificity of this technique. DW-MRI Diffusion-weighted magnetic resonance imaging (DW-MRI) is a functional nuclear magnetic resonance imaging technique that evaluates the rate of random (Brownian) motion of water in tissue, also called diffusivity. By applying diffusion-sensitizing magnetic gradients (the strength and duration of which are expressed as b-values) different levels of diffusion-weighting are obtained: from non-diffusion images (b-value = 0 s/mm2) to highly diffusion weighted images (i.e. b-value >800 s/mm2)[319]. Lesions that show high signal intensity on DW-MRI images with a high b-value thus show restricted diffusion. The apparent diffusion coefficient (ADC, in mm2/s) is calculated based on the exponential relationship between signal intensity and the corresponding b-value according to S(b)=S(0)*e-b*ADC. A high ADC represents a high degree of diffusion; a low ADC represents diffusion restriction [319, 320]. DW-MRI thus allows noninvasive quantification of tissue properties without ionizing radiation exposure for the patient. Differentiation between benign and malignant tissues by DW-MRI is based on the assumption that increased cell proliferation, cellulardensity and disorganized structures in malignant tissue restrict random motion and thus diffusion of water: a lower ADC-value, together with high signal intensity at high b-values, is more suspicious for malignancy [319, 320]. Oppositely, increased ADC-values suggest free movement of water molecules in the tissue. It is found in for example oedema, colloid follicles, fibrous tissue, haemorrhage and calcification, all of which associated with benign tissues [321]. Prior application of DW-MRI in i.e. neuroradiology, breast and lymph nodes showed high diagnostic accuracy [322, 323]. Recent exploratory studies in small cohorts of thyroid nodules found distinctively higher ADC values for benign than malignant nodules [319-321, 324-328]. A recent meta-analysis in 765 cytologically unselected thyroid nodules estimated that DW-MRI had 90% sensitivity and 95% specificity to
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