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.

Background: Large-volume lymph node metastasis (LNM) is associated with poor clinical outcomes in papillary thyroid microcarcinoma (PTMC) patients. However, sensitivity in the detection of central neck LNM on preoperative neck ultrasonography (US) is believed to be low. The aim of this study is to investigate the preoperative clinical factors associated with large-volume LNM in clinical N0 PTMC patients. Methods: In all, 2329 clinical N0 PTMC patients who underwent total thyroidectomy with prophylactic central lymph node (LN) dissection were evaluated. The LNM status of these patients was divided into three groups by the number of metastatic nodes: no LNM, small-volume LNM (≤5 metastatic LNs), and large-volume LNM (>5 metastatic LNs). The correlations between age, sex, and other clinical factors and large-volume LNM were evaluated. Results: Large-volume LNM was found in 94 (4.0%) patients. Young (<40 years old) and male patients tended to have large-volume LNM ( p for trend <0.001). Young age (odds ratio [OR] = 2.69 [confidence interval (CI) 1.64–4.32], p < 0.001) and male sex (OR = 5.79 [CI 3.67–9.10], p < 0.001) were independent risk factors for large-volume LNM in multivariate analyses. The prevalence of large-volume LNM ranged from 24% in male patients <40 years of age to only 2% in female patients aged ≥40 years. Multifocal tumors and presence of extrathyroidal extension were also considered risk factors for large-volume LNM. Conclusions: Large-volume LNM was more frequently found in young (<40 years) and male patients. These findings support the notion that surgery rather than observation may be favored in young and male clinically LN negative PTMC patients as a primary therapeutic option.

Objective: Papillary thyroid microcarcinoma (PTMC) accounts for most of the increase in thyroid cancer in recent decades. We compared clinical outcomes and surgical complications of lobectomy and total thyroidectomy (TT) in PTMC patients. Design and methods: In this retrospective individual risk factor-matched cohort study, 2031 patients with PTMC were initially included. Patients who underwent lobectomy or TT were one-to-one matched according to individual risk factors, including age, sex, primary tumor size, extrathyroidal extension, multifocality and cervical lymph node (LN) metastasis. Results: In total, 688 patients were assigned to each group. During the median 8.5 years of follow-up, 26 patients (3.8%) in the lobectomy group and 11 patients (1.6%) in the TT group had recurrences. The relative risk of recurrence was significantly less in the TT than that in the lobectomy group (hazard ratio (HR) 0.41; 95% confidence interval (CI) 0.21–0.81; P = 0.01). Most recurrences (84.6%) in the lobectomy group occurred in the contralateral lobe, and all patients were disease-free after completion of thyroidectomy. There were no significant differences in recurrence-free survival between the two groups after exclusion of contralateral lobe recurrences (HR, 2.75; 95% CI, 0.08–8.79; P = 0.08). There were significantly more patients with transient and permanent hypoparathyroidism in the TT than that in the lobectomy group (P < 0.001). Conclusions: Lobectomy could be appropriate for most patients with PTMC when there is no evidence of extrathyroidal disease in the preoperative work-up. Preoperative and postoperative imaging studies are important for patients who undergo lobectomy for PTMC, because most recurrences are in the contralateral lobe.

Known factors related to distant metastases in follicular thyroid carcinoma (FTC) included age, primary tumor size, and invasiveness. Distant metastasis is a main cause of death in FTC patients. Several studies showed that the presence of RAS mutations is also associated with poor clinical outcomes. We analyzed RAS mutations in FTC with distant metastases, FTC without a distant metastasis, follicular adenoma (FA), and nodular hyperplasia (NH). Furthermore, we elucidated the relationship between RAS mutations and clinical outcomes in FTC patients. We selected patients who underwent a thyroidectomy for FTC with distant metastases (n=28), size matched FTC specimens without a distant metastasis (n=28), FA (n=17), and NH (n=12). NRAS, HRAS, and KRAS mutations were assessed using direct sequencing. Among 85 patients, 39 patients (46%) had RAS mutations. The NRAS codon 61 mutation (n=21; 25%) was the most common point mutation. HRAS codon 61, KRAS codon 12/13, and KRAS codon 61 mutations were found in 7, 6, and 4 patients, respectively. A NRAS codon 12/13 mutation was found in only 1 patient, and a HRAS codon 12/13 mutation was not found. RAS mutations were significantly more common in the FTC than FA or NH groups. Especially, the NRAS codon 61 mutation was associated with distant metastasis in patients with FTC. The presence of a RAS mutation, especially a NRAS codon 61 mutation, was significantly associated with the distant metastasis. The NRAS codon 61 mutation status might be a potential prognostic factor in FTC patients.

Background: Increased incidence of small differentiated thyroid cancer (DTC) has emphasized the need for risk stratification and individualized disease management for these low risk DTCs. The aim was to validate a new dynamic risk stratification (DRS) system for prediction of structural recurrent/persistent disease in patients with DTC treated without radioactive iodine (RAI) remnant ablation therapy. Methods: This historical cohort study included 357 patients with DTC treated with lobectomy or total thyroidectomy without RAI therapy. We stratified patient response to initial treatment as excellent, indeterminate, biochemical incomplete, and structural incomplete according to the DRS system. Results: During a median 8.6 year of follow-up, 3.6% patients had structural recurrent DTC. The response was excellent in 71.7% patients, indeterminate in 18.5%, biochemical incomplete in 8.4%, and structural incomplete in 1.4%. There were significant differences in disease-free survival among the DRS groups (p < 0.001). The hazard ratio (HR) of recurrent/persistent disease was significantly higher in biochemical incomplete group (HR = 20.8, p < 0.001) and structural incomplete group (HR = 243.3, p < 0.001) compared with the excellent group. However, the tumor node metastasis (TNM) staging system and the American Thyroid Association (ATA) initial risk classification did not effectively predict recurrence of DTC. Conclusions: The new DRS system was effective for predicting risk of recurrent/persistent disease in patients with DTC who underwent lobectomy or total thyroidectomy without RAI remnant ablation.

Background: Anaplastic thyroid carcinoma (ATC), the most aggressive type of thyroid cancer, has no effective therapy. Due to its dismal prognosis, it is vital to understand the genetic alterations of ATC and identify effective molecular targets. Targeted next-generation sequencing was performed to investigate the mutational profile of ATC using a massive parallel sequencing approach. Methods: DNA from formalin-fixed, paraffin-embedded archival samples of 11 ATCs and normal matched pairs were used. A total of 48 genetic alterations were identified by targeted exome sequencing. These alterations were validated by mass spectrometric genotyping and direct Sanger sequencing. Results: The most commonly mutated gene was BRAF, identified in 10 samples (91%), all showing the V600E point mutation. A KRAS point mutation was observed in the one sample (9%) without the BRAF^V600E mutation. All 11 ATCs harbored BRAF or RAS mutations, reflecting the possibility that differentiated thyroid carcinomas progress to ATCs after the accumulation of mutations. A loss of function mutation of TP53 was observed in eight samples (73%), a PIK3CA mutation was observed in two samples (18%), and a frameshift mutation of PTEN was observed in one sample (9%). Twenty-eight novel mutated genes were found that had not previously been associated with ATC. Of these, loss of function mutations of NF2, KMT2D, and PKHD1 were repeatedly seen in three samples (27%), two samples (18%), and two samples (18%), respectively. Using direct Sanger sequencing, two samples (18%) were also found with a RASAL1 mutation. KMT2D and RASAL1 mutations were significantly associated with shorter ATC patient survival. Conclusions: This comprehensive analysis of ATCs using targeted massive parallel sequencing identified several novel mutations in ATCs, such as loss of function mutations of NF2 or KMT2D. Future studies are needed to confirm the role of these novel mutations as independent drivers of ATC development.