40 chapter 2 with the results of their preliminary study, Noureldine et al. demonstrated that Afirma® GEC testing had not aided surgical decision-making [173, 174]. In 93% (206/222) of the included indeterminate nodules, a ‘benign’ or ‘suspicious’ GEC result did not affect management at all: the surgical strategy would have been identical had it been based merely on clinical, cytological or radiological suspicion. However, if management changes were based on the GEC result, they were more often wrong than right: 11 times GEC-positive results inappropriately tempted physicians into more aggressive surgery, and total thyroidectomy was performed instead of the initially recommended lobectomy for nodules that proved histopathologically benign. In contrast, in just four GEC-positive cases the more aggressive surgery was appropriate and the nodule was histopathologically malignant. Also, in just one patient surgery was withheld specifically due to a negative Afirma® GEC result. In the other unresected GEC-negative nodules surgery was not clinically indicated to begin with; the negative GEC-result merely endorsed conservative management [173]. As the GEC was still a new technology when this study was conducted, it is possible that the involved physicians were unsure of the correct interpretation of the GEC results or hesitant to rely on a negative GEC result. However, clinical suspicions and physician and patient preference will always be considered when making surgical decisions. Yang et al. elegantly tried to solve the shortcoming (histological) follow-up by comparing their findings of GEC performance to a pre-GEC cohort of similar patients from their hospital in all of whom surgery was performed [50, 169]. The reported malignancy rates were comparable pre- and post-GEC implementation (18% versus 17%), and obviously relatively more surgeries were performed for benign nodules in the pre-GEC period. Assuming the true malignancy rates in the successively studied populations are indeed similar, the GEC only modestly reduced the number of futile surgeries for benign thyroid nodules from 66% to 52% [169]. Altogether, the contribution of the Afirma® GEC to the surgical decision-making may be more limited than expected based on its diagnostic accuracy. Availability, cost-effectiveness and limitations of the GEC The Afirma® GEC is currently only available for routine use in the USA. There are high demands for the FNAC specimens regarding sample preservation and shipping. Cytology is revised by Veracyte cytologists and declined if not strictly Bethesda III or IV, with 14% to 17% discordancy between local assessment and central review, comparable to known interobserver rates for thyroid cytology [26, 164, 173]. Reported rates of nondiagnostic GEC test results due to insufficient quantity or quality of the mRNA are substantial, varying from 1% to 17% [168, 170]. Insufficient mRNA quality was often caused by problems with long duration of the sample shipment to Veracyte [164, 168]. Fourth, Afirma® GEC testing is expensive and is currently marketed for $3,500 (range $1,750 to $7,000) per test [159, 169, 175]. Testing for medullary carcinoma and BRAF mutation is not included in the Afirma® GEC, but can be performed by Veracyte at additional costs [169]. Yet, ancillary BRAF mutation testing may not be relevant, as Kloos et al. found that it improved sensitivity nor specificity of the GEC [95].
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