Mutations in the TERT promoter, ALK rearrangement, and the BRAF V600E mutation are associated with aggressive clinicopathologic features in thyroid cancers. However, little is known about the impact of TERT promoter mutations and ALK rearrangement in thyroid cancer patients with a high prevalence of BRAF mutations. We performed Sanger sequencing to detect BRAF V600E and TERT promoter mutations and both immunohistochemistry and fluorescence in situ hybridization to identify ALK rearrangement on 243 thyroid cancers. TERT promoter mutations were not present in 192 well-differentiated thyroid carcinomas (WDTC) without distant metastasis or in 9 medullary carcinomas. However, the mutations did occur in 40 % (12/30) of WDTC with distant metastasis, 29 % (2/7) of poorly differentiated carcinomas and 60 % (3/5) of anaplastic carcinomas. ALK rearrangement was not present in all thyroid cancers. The BRAF V600E mutation was more frequently found in WDTC without distant metastasis than in WDTC with distant metastasis (p = 0.007). In the cohort of WDTC with distant metastasis, patients with wild-type BRAF and TERT promoter had a significantly higher response rate after radioiodine therapy (p = 0.024), whereas the BRAF V600E mutation was significantly correlated with progressive disease (p = 0.025). The TERT promoter mutation is an independent predictor for distant metastasis of WDTC, but ALK testing is not useful for clinical decision-making in Korean patients with a high prevalence of the BRAF V600E mutation. Radioiodine therapy for distant metastasis of WDTC is most effective in patients without BRAF V600E and TERT promoter mutations.

Cho U, et al. J Korean Med Sci. 2014 Aug;29(8):1054-1060. https://doi.org/10.3346/jkms.2014.29.8.1054

Background. The Warthin-like variant of papillary thyroid (WLPTC) is a rare subtype of papillary thyroid carcinoma (PTC) resembling Warthin tumors of the salivary glands. Due to its rarity, the clinicopathologic and molecular features of WLPTC remain unclear.Methods. Of the 2,139 patients who underwent surgical treatment for PTC from 2012 to 2013, 40 patients with WLPTC were identified and compared to 200 consecutive patients with classic PTC.BRAFmutation was tested with pyrosequencing.Results. There were no significant differences in age, predilection for women, multifocality, extrathyroidal extension, or lymph node metastasis between WLPTC and classic PTC. However, WLPTCs were more commonly associated with Hashimoto’s thyroiditis than classic PTCs (93% versus 36%, resp.,P< 0.001) and showed significantly lower rate ofBRAFmutation when compared to classic PTCs (65% versus 84%, resp.,P= 0.007). In classic PTC, the frequency ofBRAFmutations was negatively correlated with coexisting Hashimoto’s thyroiditis. When we compared WLPTC and classic PTC in the patients with coexisting Hashimoto’s thyroiditis, there were no significant differences in clinicopathologic characteristics or theBRAFmutational rate between the two groups.Conclusions. Patients with WLPTC have similar demographic, clinical, pathologic, and molecular characteristics to those with classic PTC coexisting with Hashimoto’s thyroiditis.

Background: Although most differentiated thyroid carcinomas (DTCs) have indolent behavior, DTCs with distant metastasis have a poor prognosis. However, there are no validated markers that predict the risk of distant metastasis and the prognosis of DTC. We aimed to develop a genetic classifier for predicting the outcomes of DTC patients with distant metastases. Methods: Targeted deep sequencing of 157 cancer-related genes was performed for 61 DTCs with distant metastases. A candidate mutation was validated with independent thyroid cancer samples using digital polymerase chain reaction. Results: The most frequently mutated gene in the 61 DTCs was BRAF ( n = 31, 51%), followed by TERT promoter ( n = 28, 46%), NRAS ( n = 13, 11%), PLEKHS1 promoter ( n = 6, 10%), and STK11 ( n = 6, 10%) mutations. PLEKHS1 promoter mutations were more common in the radioactive iodine (RAI)-refractory cases ( p = 0.003). Losses of 9q and 11q were associated with RAI-refractory disease ( p = 0.002) and cancer-specific mortality ( p = 0.028), respectively. In multivariate analysis, bone metastasis (adjusted odds ratio [aOR] = 15.17, 95% confidence interval [CI 3.38–68.06], p < 0.001) and at least one mutation in the TERT promoter, the PLEKHS1 promoter, or TP53 (aOR = 7.64 [CI 1.78–32.76], p = 0.006) remained significant factors associated with RAI-refractoriness. In independently collected papillary thyroid carcinomas without initial distant metastasis ( n = 75), a PLEKHS1 promoter mutation was only found in one case that developed distant metastasis during the follow-up period. We developed a genetic classifier consisting of BRAF , RAS , the TERT promoter, the PLEKHS1 promoter, and TP53 for categorizing the prognosis of patients with DTC with distant metastasis. In the poor-prognosis group, 61% of the patients were RAI-refractory and death occurred in 21% during the follow-up. In the intermediate-prognosis group, 29% were RAI-refractory, but no death occurred. In the good-prognosis group, all patients were RAI-responsive and no death occurred. Conclusions: Mutations in the PLEKHS1 promoter are a novel genetic marker of aggressive DTC. Our genetic classifier can be useful for predicting RAI-refractory disease and poor prognosis in DTC patients with distant metastases.

Background. Most patients with a preoperative diagnosis of thyroid follicular neoplasm (FN) undergo diagnostic surgery to determine whether the nodule is benign or malignant. Point mutations atNRAScodon 61 are the most common mutations observed in FN. However, the clinical significance ofNRASmutation remains unclear.Methods. From 2012 to 2013, 123 consecutive patients undergoing thyroidectomy for FN were evaluated prospectively. Molecular analyses forNRAScodon 61 were performed with pyrosequencing.Results. The overall malignancy rate in FN was 48.8% (60/123). Of 123 FNs, 33 (26.8%) were positive for theNRASmutation. The sensitivity, specificity, positive predictive value, and negative predictive value of aNRASmutation-positive FN specimen to predict malignancy were 37%, 83%, 67%, and 58%, respectively. Patients with aNRAS-positive FN had a higher malignancy rate in additional thyroid nodules beyond the FN than patients with a NRAS-negative FN. The overall malignancy rate of patients with a NRAS-positive FN was significantly higher than that of patients with a NRAS-negative FN (79% versus 52%;P= 0.008).Conclusions. Determining NRAS mutation status in FN helps to improve the accuracy of thyroid cancer diagnosis and to predict cancer risk in accompanying thyroid nodules.