Despite a number of studies exploring the diagnostic value of GEC and Thyroseq® V2, the current published literature includes discrepancies in the follow-up of molecular marker negative nodules and their consideration as a benign pathology (85, 86). Consequently, this may lead to inaccuracies in diagnostic value calculation. A systematic review by Duh et al. (85) highlighted these issues. They included 12 studies and discussed the exclusion of cytologically indeterminate, GEC benign nodules from diagnostic performance calculations (malignant versus benign), leading to an erroneous decrease in Sp and NPV. This is due to the lack of surgical pathology specimens to establish a definitive diagnosis, as well as a lack of follow-up of GEC benign nodules to establish a reference diagnosis. To establish a diagnostic “reference standard” in these nodules that have not undergone surgery and include them in calculations, the authors argue that they should be considered as “true negative” only if no suspicious changes are noted on scheduled interval ultrasound examinations. However, even the natural history of benign thyroid nodules has been described to involve size changes. Indeed, a 5-year prospective study involving 1,567 sonographically or cytologically benign thyroid nodules showed nodule growth in 11.1% (87). However, thyroid cancer was diagnosed in five original nodules (0.3%), of which, only two had an increase in size. Furthermore, a retrospective study ranging from 1 month to 5 years, reported that 39% of the 268 benign thyroid nodules showed at least a 15% change in nodule volume (88). Only one of the 74 repeat-FNAs was malignant. The authors conclude that an increase in nodule volume alone is not a reliable predictor of malignancy.