Medici, MarcoKwong, NorraAngell, Trevor E.Marqusee, EllenKim, MatthewFrates, MaryBenson, CarolCibas, EdmundBarletta, JustineKrane, JeffreyRuan, Daniel T.Cho, NancyGawande, AtulMoore, FrancisAlexander, Erik2015-09-012015Medici, M., N. Kwong, T. E. Angell, E. Marqusee, M. I. Kim, M. C. Frates, C. B. Benson, et al. 2015. “The variable phenotype and low-risk nature of RAS-positive thyroid nodules.” BMC Medicine 13 (1): 184. doi:10.1186/s12916-015-0419-z. http://dx.doi.org/10.1186/s12916-015-0419-z.1741-7015http://nrs.harvard.edu/urn-3:HUL.InstRepos:21459031Background: Oncogenic mutations are common in thyroid cancers. While the frequently detected RAS-oncogene mutations have been studied for diagnostic use in cytologically indeterminate thyroid nodules, no investigation has studied such mutations in an unselected population of thyroid nodules. No long-term study of RAS-positive thyroid nodules has been performed. Methods: We performed a prospective, blinded cohort study in 362 consecutive patients presenting with clinically relevant (>1 cm) thyroid nodules. Fine needle aspiration cytology and mutational testing were obtained for all nodules. Post-operative histopathology was obtained for malignant or indeterminate nodules, and benign nodules were sonographically followed. Histopathological features were compared between RAS- and BRAF-positive malignancies. RAS-positive benign nodules were analyzed for growth or cellular change from prior aspirations. Results: Overall, 17 of 362 nodules were RAS-positive. Nine separate nodules were BRAF-positive, of which eight underwent surgery and all proved malignant (100 %). Out of the 17 RAS-positive nodules, ten underwent surgery, of which eight proved malignant (47 %). All RAS-positive malignancies were low risk – all follicular variants of papillary carcinoma, without extrathyroidal extension, metastases, or lymphovascular invasion. RAS-positivity was associated with malignancy in younger patients (P = 0.028). Of the nine RAS-positive benign nodules, five had long-term prospective sonographic follow-up (mean 8.3 years) showing no growth or signs of malignancy. Four of these nodules also had previous aspirations (mean 5.8 years prior), all with similar benign results. Conclusions: While RAS-oncogene mutations increase malignancy risk, these data demonstrate a low-risk phenotype for most RAS-positive cancers. Furthermore, cytologically benign, yet RAS-positive nodules behave in an indolent fashion over years. RAS-positivity alone should therefore not dictate clinical decisions.en-USJournal Article2015-09-0110.1186/s12916-015-0419-z