The variable phenotype and low-risk nature of RAS-positive thyroid nodules

Abstract

BackgroundOncogenic 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.MethodsWe 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.ResultsOverall, 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.ConclusionsWhile 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.

Young Investigator Challenge: Molecular testing in noninvasive follicular thyroid neoplasm with papillary‐like nuclear features

“…All NIFTPs that were sent for targeted mutation analysis harbored RAS mutations. The findings of RAS mutations in NIFTPs is consistent with the literature, which documents the prevalence of RAS mutations in follicular‐patterned tumors …”

Risk of malignancy and neoplasia predicted by three molecular testing platforms in indeterminate thyroid nodules on fine‐needle aspiration

“…Prior to the change in nomenclature, a prospective study by Medici et al analyzed the behavior of RAS‐positive thyroid nodules. All RAS‐positive malignancies in their cohort demonstrated very low‐risk characteristics . They were diagnosed as FVPTC with no evidence of capsular or lymphovascular invasion, extrathyroidal extension, or metastases.…”

“…They were diagnosed as FVPTC with no evidence of capsular or lymphovascular invasion, extrathyroidal extension, or metastases. It is likely that many of these neoplasms would now be described as NIFTP . Paulson et al also conducted a study to review the slides of previously diagnosed FVPTC and determine how many met criteria for NIFTP.…”

Molecular Testing of Thyroid Nodules: A Review of Current Available Tests for Fine-Needle Aspiration Specimens

“…The PPV is expected to decrease for all currently available molecular tests, as NIFT-P was considered a malignant neoplasm in the validation studies and subsequent studies. For instance, in a recent study, Medici et al 51 found that 17 of the 362 thyroid nodules were RAS-positive by miRInform Thyroid molecular test. The results showed that 7 of 10 RAS-positive resected nodules represented NIFT-Ps.…”