BackgroundMutations 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.MethodsWe 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.ResultsTERT 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).ConclusionsThe 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.

The cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is a rare thyroid neoplasm characterized by unique morphologic findings and association with familial adenomatous polyposis. The biologic behavior of this variant has been reported to behave similarly to classic PTC. We report a rare sporadic case of CMV-PTC occurring in a 45-year-old female with multiple lymph nodes and bone metastases, which were detected after total thyroidectomy and radioactive iodine remnant ablation. Molecular analyses of primary thyroid and metastatic tumor tissues revealed a telomerase reverse transcriptase (TERT) promoter mutation, but absence of BRAF, KRAS, NRAS, HRAS, and PIK3CA mutations. Over a 4-year follow-up period, structurally identifiable bone metastases were persistent, but serial post-operative serum thyroglobulin levels remained undetectable in the absence of thyroglobulin antibody. The literature was reviewed. This is the first case of aggressive CMV-PTC showing TERT promoter mutation. TERT promoter mutations may help in predicting aggressive clinical behavior in CMV-PTC. Postoperative serum thyroglobulin measurement may have no impact on clinical decision-making in this type of tumor.

Follicular-patterned tumors of the thyroid gland are characterized by a predominantly follicular growth pattern. They frequently harbor RAS mutations, not BRAF mutations. Technological advances in molecular testing have discovered novel RAS-type mutations. However, clinical significance of these mutations remains unknown. We investigated the prevalence and clinical impact of mutations of BRAF, NRAS, HRAS, KRAS, EZH1, EIF1AX, and TERT genes by Sanger sequencing in a series of 201 follicular-patterned thyroid tumors including follicular adenoma (n = 40), Hürthle cell adenoma (n = 54), noninvasive follicular thyroid neoplasms with papillary-like nuclear features (n = 50), follicular thyroid carcinoma (n = 40), Hürthle cell carcinoma (n = 10), and poorly differentiated thyroid carcinoma arising in a well-differentiated follicular neoplasm (n = 7), and 120 classic papillary carcinoma. Two hotspots of EZH1 mutations were only found in RAS-negative follicular-patterned tumors. EZH1 mutations were detected in 3% of follicular adenoma and in 20% of Hürthle cell adenoma, and one minimally invasive Hürthle cell carcinoma. Thyroid tumors with EZH1 mutations reported in the literature were benign in most cases. Otherwise, they were minimally invasive or noninvasive cancer. EIF1AX mutation was found in one follicular adenoma. We confirmed the presence of RAS mutations and BRAF K601E mutation in benign, borderline, and malignant follicular-patterned tumors. No BRAF V600E was found in all follicular-patterned tumors. This study also confirmed the occurrence of TERT promoter mutations in high-risk thyroid cancers. These genetic markers can be used for the diagnostic purpose and risk stratification of thyroid nodules.

Cyclin D1 protein is aberrantly overexpressed in thyroid cancers, but mutations of the CCND1 gene are rare in these tumors. We investigated the CCND1 rs9344 (G870A) polymorphism and the expression profiles of wild-type CCND1a and shortened oncogenic isoform CCND1b at the mRNA and protein levels in 286 thyroid tumors. Genotype AA of rs9344 was associated with high expression of CCND1b mRNA and was more frequently found in thyroid cancer than in benign tumors. The mRNA expression levels of CCND1b were higher in papillary thyroid carcinoma (PTC) than in benign or other malignant tumors. However, the expression of CCND1a mRNA showed no association with the parameters. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was distinguished from PTC by low expression of CCND1b at mRNA and protein levels. We further observed that cyclin D1b immunostaining helped to avoid the misdiagnosis of classic PTC with predominant follicular pattern as NIFTP in a separate cohort. Nuclear cyclin D1b expression was associated with aggressive clinicopathologic features in PTC. These findings suggest that cyclin D1b overexpression can be used as a diagnostic and predictive biomarker in thyroid tumors and may be functionally involved in the development and progression of the disease.

No abstract

Papillary thyroid carcinoma (PTC) is a heterogeneous tumor with various histological and molecular subtypes. EHD2 is involved in endocytosis and endosomal recycling. This study aimed to investigate the prognostic significance of EHD2 expression in PTC and develop a new model for predicting persistent/recurrent disease after thyroidectomy. Pathologic slides of 512 consecutive patients with PTC ≥ 1 cm were retrospectively reviewed. BRAF mutation analysis and immunohistochemistry for EHD2 were performed. Clinical significance of EHD2 mRNA expression was analyzed in 388 PTC patients using The Cancer Genome Atlas dataset. The presence of dyscohesive cells and psammoma bodies were found have significant association with persistent/recurrent disease (p = 0.049 and p = 0.038, respectively). The best discrimination of disease-free survival was found by dividing patients into three prognostic groups based on the following two risk factors according to the size category: psammoma bodies ≥ 4 and dyscohesive cells (≥ 1% and ≥ 20% in PTCs of < 2.0 cm and ≥ 2.0 cm, respectively). In PTCs of ≥ 2.0 cm, patients with the two risk factors had a hazard ratio of 13.303 (p = 0.005) compared to those without risk factors. High expression level of EHD2 was associated with BRAF V600E (p < 0.001), presence of dyscohesive cells (p = 0.010), and absence of psammoma bodies (p = 0.001). Increased EHD2 mRNA expression level was associated with extrathyroidal extension (p < 0.001), pT3-4 (p < 0.001), lymph node metastasis (p < 0.001), higher risk of recurrence (p < 0.001), and BRAF V600E (p < 0.001). Our prognostic model is useful for predicting persistent/recurrent disease after surgery of PTC. EHD2 mRNA expression could be a novel prognostic marker for PTC patients.

No abstract

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 at NRAS codon 61 are the most common mutations observed in FN. However, the clinical significance of NRAS mutation remains unclear. Methods. From 2012 to 2013, 123 consecutive patients undergoing thyroidectomy for FN were evaluated prospectively. Molecular analyses for NRAS codon 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 the NRAS mutation. The sensitivity, specificity, positive predictive value, and negative predictive value of a NRAS mutation-positive FN specimen to predict malignancy were 37%, 83%, 67%, and 58%, respectively. Patients with a NRAS-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.