42 chapter 2 GEC in Hürthle cell cytology Brauner et al. specifically validated the Afirma® GEC in 72 cytology samples suspicious for Hürthle cell neoplasm. They demonstrated that GEC testing could accurately have reduced the number of futile surgeries, although through a less profound reduction than in non-oncocytic indeterminate thyroid nodules [170]. Similar results were noticed in other studies: despite a relatively low risk of malignancy, the majority of Hürthle cell nodules were GEC-positive. Regardless of good sensitivity, this unfavourable benign call rate in Hürthle cell cytology limits diagnostic efficacy in these nodules, increasing the number needed to test and negatively affecting possible cost-effectiveness [164, 169, 171, 173, 180, 182]. Diagnostic accuracy of the GEC would likely improve if Bethesda IV cytology suspicious for a Hürthle cell lesion was excluded from GEC testing. Otherwise, similar to the additional testing for medullary carcinoma, adaptations should be made to the Afirma® GEC to improve its clinical utility for Hürthle cell lesions. In conclusion, it is generally assumed that the Afirma® GEC accurately reclassifies approximately two out of five indeterminate thyroid nodules as benign with published sensitivities ranging between 83% and 100% and similar test performance in Bethesda III and IV nodules. Withholding diagnostic surgery from these patients seems safe [168, 169, 172, 182]. However, the diagnostic strength and potential cost-utility of Afirma® GEC strongly rely on its NPV – thus on the prevalence of malignancy and benign call rate in the targeted population. There are important concerns regarding the currently insufficient number of clinical validation studies with adequate rates of histopathological confirmation or long-term clinical follow-up. Physicians are strongly advised to locally validate Afirma® GEC test performance before considering test implementation in daily practice. Nonetheless, further large validation studies on the Afirma® GEC may soon become obsolete, as an updated version of the test, the Gene Sequencing Classifier (Veracyte Inc., South San Francisco, CA, USA), is currently being put into operation. Improved diagnostic accuracy is anticipated, with specific attention to the differentiation of Hürthle cell nodules. MicroRNA First described in thyroid cytology in 2006, evaluation of the expression levels of microRNA (also called miRNA) is among the newer and more promising approaches to differentiate between benign and malignant thyroid neoplasms [183, 184]. MicroRNAs are small endogenous noncoding ribonucleic acids (RNAs) of approximately 22 nucleotides in length. As negative regulators (i.e. silencers) of protein synthesis at a post-transcriptional level, they are involved in many intracellular processes, including cell growth, differentiation and proliferation. Dysregulation of microRNA expression is found in almost all types of human cancers [185]. It reflects the deregulated expression of oncogenes and tumour suppressor genes [184, 186-188]. MicroRNA overexpression is present
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