Background: The recent increase in the incidence of thyroid cancer has been mainly attributed to papillary thyroid microcarcinomas (PTMCs), and many studies have suggested conservative strategies for the diagnosis and treatment of PTMC. However, PTMCs may be associated with distant metastasis. This study aimed to evaluate the clinicopathological features and identify the risk factors for distant metastasis in patients with PTMCs. Methods: The medical records of 8808 patients who were diagnosed with PTMC from 1999 to 2012 were reviewed, and 12 (0.1%) patients with distant metastasis were identified. Forty-one PTMC patients who initially had lateral cervical lymph node (LN) metastasis and were cured with no evidence of a distant metastasis were also selected as a control group. Results: Of the 12 patients with distant metastasis, nine had synchronous metastasis and three had metachronous metastasis. All 12 patients had primary tumors >0.5 cm and cervical LN metastasis at initial surgery. Ten patients had clinically apparent lateral cervical LN metastases, while two patients had only microscopic involvement of a central LN. Four patients died of thyroid carcinoma. Disease-specific mortality was associated with old age, large metastatic LNs with extranodal extension, and aggressive pathologic subtype of metastatic LNs. When the clinicopathological features of the patients with distant metastasis were compared with the control patients, the presence of extranodal extension and change to an aggressive pathologic subtype of metastatic LNs were significantly associated with distant metastasis and persistent structural distant PTMC metastasis. Conclusions: Most patients with PTMC demonstrate excellent clinical outcomes, and distant metastases rarely occur. However, distant metastasis of PTMC can be fatal. Performing a meticulous pathologic examination of metastatic LNs to identify the presence of extranodal extension and the pathologic subtype of metastatic LNs helps to assess the risk of a distant metastasis in patients with PTMC.

Aggressive variants of papillary thyroid carcinoma (PTC) have been described with increasing frequency and are associated with unfavorable clinical outcomes. However, limited data exist on the comprehensive genetic profile of these variants. We performed targeted next-generation sequencing in 36 patients with aggressive variants of PTC and compared it to PTC from The Cancer Genome Atlas (TCGA) project and poorly differentiated thyroid cancers (PDTCs)/anaplastic thyroid cancers (ATCs) from the Memorial Sloan Kettering Cancer Center (MSKCC). BRAF mutation was the most prevalent (89%) in aggressive variants of PTC compared to that in other thyroid cancers. RAS mutation was identified in one patient (3%), which was less frequent than in others. TERT promoter mutation (17%) ranged between that of PTCs (9%) and PDTCs (40%). Tumor suppressor genes, ZFHX3, TP53, and CHEK2, were mutated in 14%, 3%, and 6% of aggressive variants of PTC, respectively. The mutation rate of TP53 (3%) was significantly higher than that of PTCs (0.7%) and lower than that of ATCs (73%). Mutations in three functional groups, histone methyl transferases, SWI/SNF chromatin remodeling complex, and the PI3K/AKT/mTOR pathway, were present in 11%, 14%, and 11% of samples, respectively. In conclusion, aggressive variants of PTC had higher BRAF and lower NRAS mutation prevalence than other thyroid cancers. The prevalence of mutations in the TERT promoter, TP53, and genes encoding three functional groups ranged between that of PTCs and PDTCs/ATCs.

Purpose: Radiofrequency ablation (RFA) and ethanol ablation (EA) are effective and safe for benign symptomatic thyroid nodules (BSTNs). However, relatively little is known about the effects of these procedures on patients’ quality of life (QoL). This prospective, multicenter study evaluated the effects of RFA and EA on changes in thyroid-specific QoL in patients with BSTNs and assessed the volume reduction and safety of these procedures.Methods: Eighty-six consecutive patients with 86 BSTNs were prospectively included from two medical centers. RFA was performed for 55 BSTNs with solidity ≥50% and EA was performed for 31 BSTNs with solidity <50%. QoL was evaluated using an 11-scale, multiple-choice thyroid-specific QoL questionnaire. Nodule characteristics and QoL were evaluated at diagnosis and 1, 6, and 12 months after treatment. Overall QoL was rated from 0 (good) to 4 (poor).Results: The mean longest size and volume of the index nodule were 4.2±1.5 cm and 21.6±22.1 mL, respectively. Patients received 1.1 treatments on average (range, 1 to 2). Significant post-treatment volume reductions were noted; however, the EA group showed a higher volume reduction than the RFA group at 1 (78.7%-16.1% vs. 49.1%-15.8%), 6 (86.3%-21.7% vs. 73.0%-14.5%), and 12 (90.9%-14.9% vs. 80.3%-12.4%) months. The score for each scale of the QoL questionnaire improved significantly during follow-up (all P<0.001). Overall QoL improved significantly, 1.7±0.9 at diagnosis to 0.6±0.7 at the 12-month follow-up (P<0.001). There were no major complications.Conclusion: Both RFA and EA are safe and effective in reducing nodule volume and improving thyroid-specific QoL in patients with BSTNs.

Background: Catabolism of serine via serine hydroxymethyltransferase2 (SHMT2) through the mitochondrial one-carbon unit pathway is important in tumorigenesis. Therefore, SHMT2 may play a role in thyroid cancer. Methods: Thyroid tissue samples and The Cancer Genome Atlas (TCGA) database were used to evaluate SHMT2 expression in thyroid tissues and the association with clinical outcomes. Results: SHMT2 protein expression was evaluated in thyroid tissues consisting of 52 benign nodules, 129 papillary thyroid carcinomas (PTC) and matched normal samples, and 20 anaplastic thyroid carcinomas (ATC). ATCs presented the highest (95.0%) positivity of SMHT2 protein expression. PTCs showed the second highest (73.6%) positivity of SHMT2 expression, which was significantly higher than that of benign nodules (19.2%, P = 0.016) and normal thyroid tissues (0%, P < 0.001). Analysis of TCGA data showed that SHMT2 messenger RNA (mRNA) expression was significantly higher in tumors than in normal tissues (P < 0.001). When we classified thyroid cancer into high and low groups according to SHMT2 mRNA expression levels, the thyroid differentiation score for the high SHMT2 group was significantly lower than that of the low SHMT2 group (P < 0.001). There was also a significant correlation between SHMT2 mRNA expression and the stemness index (r = 0.41, P < 0.001). The high SHMT2 group had more advanced TNM stages and shorter progression-free survival rates than the low SHMT2 group (P < 0.01 and P = 0.007, respectively). Conclusion: SHMT2 expression is higher in thyroid cancers than normal or benign tissues and is associated with de-differentiation and poor clinical outcomes. Thus, SHMT2 might be useful as a diagnostic and prognostic marker for thyroid cancer.