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Background: Several cancers show increased levels of lactate dehydrogenase A (LDHA), which are associated with cancer progression. However, it remains unclear whether LDHA levels are associated with papillary thyroid cancer (PTC) aggressiveness or with the presence of the PTC prognostic marker, the BRAFV600E mutation. This study aimed to evaluate the potential of LDHA as a PTC prognostic marker., Methods: LDHA expression was examined in 83 PTC tissue specimens by immunohistochemistry. Human thyroid cell lines were genetically manipulated to overexpress BRAFV600E or were treated with a BRAF-specific short hairpin RNA (shBRAF), whose effects on LDHA expression were evaluated by Western blotting. Data from 465 PTC patients were obtained from The Cancer Genome Atlas (TCGA) database and analyzed to validate the in vitro results., Results: LDHA was aberrantly overexpressed in PTC. Intense immunostaining for LDHA was observed in PTC specimens carrying mutated BRAF, whereas the intensity was less in wild-type BRAF samples. Overexpression of BRAFV600E resulted in LDHA upregulation, whereas treatment with shBRAF downregulated LDHA in human thyroid cell lines. Furthermore, LDHA mRNA expression was significantly elevated and associated with BRAFV600E expression in thyroid cancer tissues from TCGA database. Additionally, LDHA overexpression was found to be correlated with aggressive clinical features of PTC, such as lymph node metastases and advanced tumor stages., Conclusion: LDHA overexpression is associated with the BRAFV600E mutation and an aggressive PTC behavior. Therefore, LDHA may serve as a biomarker and therapeutic target in PTC.

Purpose: Papillary thyroid microcarcinoma (PTMC) has an excellent prognosis due to its indolent features. Only few studies have assessed the clinical factors that can predict lateral neck lymph node metastasis (LLNM) in patients with PTMC. This study aimed to examine the clinicopathological factors associated with LLNM in patients with PTMC., Methods: We reviewed medical records of 3578 patients with PTMC that was ≤1 cm in diameter on final pathology at Yonsei University Hospital between January 2015 and December 2017. The patients were divided into two groups (metastasis group [n = 157] and no metastasis group [n = 3421])., Results: The proportion of patients with multifocality, extrathyroidal extension (ETE), and central node metastasis was significantly higher in metastasis group (p < 0.001, p < 0.001 and p < 0.001, respectively), and the mean tumor size was relatively larger in metastasis group than in no metastasis group (0.7 ± 0.2 vs. 0.6 ± 0.2 cm, p < 0.001). However, no statistically significant differences were observed in the tumors harboring BRAF mutation between the two groups (84.8% vs. 80.6%, p = 0.199). Multivariate analysis indicated that the significant risk factors of LLNM include ETE (odds ratio [OR]: 1.904, 95% confidence interval [CI]: 1.267-2.861), multifocality (OR: 2.255, 95% CI: 1.544-3.293), and central node metastasis (OR: 7.768, 95% CI: 4.869-12.395), but not BRAF mutation (OR: 0.542, 95% CI: 0.337-0.874)., Conclusion: Approximately 4.4% of patients with PTMC presented with LLNM at the time of diagnosis. Moreover, the significant risk factors of LLNM include central node metastasis, ETE, and multifocal disease but not BRAF mutation.

Background: Active surveillance is an alternative management for patents with low-risk papillary thyroid microcarcinoma (PTMC); however, there is an absence of specific molecular markers that predict its progression. We compared gene expression patterns between PTMC with lateral neck-node metastasis (N1b) and PTMC-lacking nodal metastasis (N0)., Methods: We performed oligonucleotide microarray analysis in three PTMCs without cervical lymph-node metastases (N0), and five PTMCs with lateral neck-node metastasis (N1b) at initial diagnosis, using an Illumina HumanHT-12 v4.0 Expression BeadChip. Quantitative real-time PCR (qPCR) and western blot analysis confirmed microarray data. We performed immunohistochemistry (IHC) to confirm protein overexpression in samples from 20 N0 and 24 N1b PTMC patients who underwent thyroidectomy., Results: Microarray analyses identified 52 probes corresponding to 45 genes. Expression of these genes differed significantly between the two PTMC groups. Forty genes were significantly upregulated and five genes were downregulated in N1b PTMC compared to N0. Four genes related to epithelial-to-mesenchymal transition (EMT) and stem cell markers, including ALDH1A3, TM4SF1, PROM1, and CAV1 were significantly upregulated in N1b PTMCs. Real-time qPCR confirmed this expression and western blot analysis confirmed higher expression of ALDH1A3, TM4SF1, PROM1, and CAV1 in N1b than in N0 PTMCs. IHC indicated overexpression of ALDH1A3 and CAV1 in N1b compared to N0 PTMCs., Conclusions: Genes related to EMT and thyroid cancer stem cell-like properties are upregulated in early extensive lymphatic spread of PTMC., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The aim of this study is to compare the feasibility and oncologic safety of Single-incision, gasless, Endoscopic trans-axillary bilateral Total thyroidectomy (SET) with open cervical total thyroidectomy in patients with papillary thyroid carcinoma (PTC)., Materials and Methods: From March 2008 to December 2012, PTC patients underwent bilateral total thyroidectomy. Conventional, open surgery was performed on 538 patients (Group O) and endoscopic surgery was performed on 200 patients (Group E). We analyzed the patient's clinicopathologic, postoperative complications, and surgical completeness., Results: The mean ages of the patients were 48.9 ± 0.5 (range = 24-77) in Group O and 39.5 ± 0.8 (range = 17-73) in Group E with statistical significance (P < .001). Percentage of female patients were 74.3% in Group O and 96.0% in Group E with statistical significance (P < .001). The postoperative hospital stay in Group O was significantly longer than Group E (4.60 ± 0.05 versus 3.30 ± 0.05; P < .001). The operation time in Group E was significantly longer than Group O (93.9 ± 1.3 versus 142.6 ± 3.3; P < .001). More transient hypocalcemia was found in Group O compared to Group E with statistical significance (28.1% versus 22.4%; P < .001). There were no significant differences with respect to permanent hypocalcemia, permanent recurrent laryngeal nerve palsy, seroma, and hematoma. The mean 1 year-stimulated sTg was 0.23 ± 0.03 and 0.18 ± 0.02 in Group O and E, respectively. Tumor recurrence during short-term follow-up at neck ultrasonography (1 year) was detected in 4 patients in Group O., Conclusion: SET is safe and effective, not only for low-risk patients with early-detected cancer, but also for selected cases of advanced cancer.

Background: Robotic modified radical neck dissection (MRND) using a gasless transaxillary approach has been reported to be a safe and meticulous technique in patients with papillary thyroid carcinoma (PTC) and lateral neck node metastasis (N1b). Few studies, however, have attempted to assess the long-term oncologic outcomes of robotic MRND in these patients. This study aimed to compare perioperative and 5-year oncologic outcomes of robotic MRND with conventional open procedures in patients with N1b PTC., Methods: Between September 2007 and February 2010, 193 patients with N1b PTC underwent total thyroidectomy and MRND by a single surgeon. Of these, 42 (21.8 %) underwent robotic procedures and 151 (78.2 %) underwent conventional open procedures. All patients received 3.7- to 5.5-GBq radioactive iodine (RAI) ablation, post-therapy whole-body scans (TxWBSs), and diagnostic WBS (DxWBSs) during follow-up. An exact 1:3 matching for age and stage was performed to minimize selection bias, and perioperative and 5-year oncologic outcomes were compared in the matched groups., Results: The mean follow-up period was 66.0 months (range 60-90 months). Number of retrieved cervical lymph nodes (LNs) (p = .102) and postoperative ablation success rates (p = .864) were similar between the two groups. TSH-suppressed serum Tg concentrations after 5 years (0.7 ± 1.5 vs. 2.4 ± 14.1 ng/ml; p = .471) and recurrence rates in the robotic and open groups (1/41 [2.4 %] vs. 3/102 [2.9 %]; p = .864) were similar for the 5-year follow-up period. Four patients experienced recurrence: Three exhibited regional lymph node metastasis, and one showed bilateral lung metastases., Conclusion: The perioperative and 5-year oncologic outcomes were similar after robotic and conventional open MRND. Large, prospective randomized controlled trials with long-term follow-up data are needed to validate these results.

Background: The 2015 American Thyroid Association (ATA) management guidelines for adult patients with differentiated thyroid cancer propose the use of the modified initial risk stratification and response to therapy re-stratification systems. This study was conducted to validate the practicality of the revised guidelines for predicting tumor recurrence in patients with differentiated thyroid cancer., Methods: Patients with papillary thyroid cancer (n = 2425) who underwent total thyroidectomy with central neck node dissection with or without modified radical neck node dissection at a single institution between October 1985 and July 2009 were retrospectively enrolled. The accuracy of three different risk-stratification strategies for predicting disease-free survival, set out in the 2009 and 2015 ATA management guidelines, was assessed: the initial risk stratification (ATA 2009-RSS), the modified initial risk stratification (ATA 2015-RSS), and the response to therapy re-stratification (ATA 2015-RTR)., Results: After applying the ATA 2015-RSS, 258/1913 (13.5%) of patients originally designated as intermediate risk by the ATA 2009-RSS were designated as low risk. This was mainly due to the small number of metastatic lymph nodes. Recurrence was detected in 136 (5.6%) patients during follow-up. Of the 2425 cases examined, 375 were designated as low risk by the ATA 2009-RSS, with a recurrence rate of 1.1%. However, the ATA 2015-RSS designated 633 (26.1%) cases as low risk, with a recurrence rate of 0.9%. Implementing the ATA 2015-RTR predicted an excellent response in 1597 (65.9%) cases, with a recurrence rate of 1.1%. According to the proportion of variance explained (PVE), the Akaike information criterion, Harrell's c index, and integrated area under the curve, comparing the predictive accuracy of the ATA 2009-RSS, ATA 2015-RSS, and ATA 2015-RTR revealed that the ATA 2015-RTR was a superior predictor of recurrence., Conclusions: A proportion of patients designated as intermediate risk by the ATA 2009-RSS were designated as low risk by the ATA 2015-RSS. The ATA 2015-RTR may be the most accurate predictor of risk of recurrence.

Background: The prevalence of papillary thyroid cancer (PTC) is thought to be related to obesity, which affects the prognosis for PTC patients. However, the mechanisms implicated in the relationship between obesity and PTC is a matter for debate. In this study, we aimed to gain insight into the relationship between obesity and the clinicopathological features of PTC, including the BRAFV600E mutation., Methods: The medical records of 1121 PTC patients were reviewed and the relationships between anthropometric factors, biochemical parameters, and clinicopathological parameters, including BRAFV600E mutation status, were analyzed., Results: Body mass index (BMI) showed a strong association with advanced TNM stage (p < 0.001) and BRAFV600E mutation status (p = 0.008). We also found that BRAFV600E (+) patients had a higher body weight (p = 0.024) and a higher BMI (p = 0.003) than patients with BRAFV600E (-) PTC. In addition, BRAFV600E (+) PTC patients had a significantly higher incidence of extrathyroidal extension (p = 0.025) and more advanced T, N, TNM stage (p < 0.001) than BRAFV600E (-) PTC patients. Consistent with this observation, female BRAFV600E (+) PTC patients had a higher BMI (p = 0.011) and more aggressive tumor behaviors than female BRAFV600E (-) PTC patients. In multivariate analysis, BMI was persistently associated with BRAFV600E mutation in the entire cohort (odds ratio [OR] 1.387; 95 % CI 1.036-1.859; p = 0.028) and in the female subcohort (OR 1.221; 95 % CI 1.014-1.631; p = 0.046)., Conclusion: The positive association between BMI and BRAFV600E supports the hypothesis that excessive bodyweight influences tumor progression.

Background: Acellular dermal matrix (ADM) has been used for antiadhesion formation along with wound healing in various surgical fields., Objective: The aim is to assess the efficacy of ADM implantation in the prevention of postoperative scars and adhesions after conventional, open, total thyroidectomy., Materials and Methods: Forty-four patients with papillary thyroid carcinoma undergoing thyroidectomy were randomly assigned to the study (ADM implantation) or control group (without ADM). Global photographic assessment, Vancouver scar scale (VSS), objective scar assessment, and swallowing impairment index were assessed at baseline, immediately after surgery, and at 1 and 2 months after surgery., Results: Nineteen control and 20 study group participants completed the study. The mean VSS score of the study group was significantly lower than the controls at both 1 month (3.06 ± 1.25 vs 4.41 ± 1.54, respectively) and 2 months (2.76 ± 1.56 vs 4.35 ± 1.58, respectively) after surgery. Scar quality measures (mean melanin and erythema indexes) were significantly lower in the study group compared with controls. Study group participants had significantly lower swallowing impairment scores than controls. The mean postoperative hospitalization of both groups was not significantly different., Conclusion: Acellular dermal matrix-assisted implants appear to improve post-thyroidectomy scar and swallowing impairments without delays in operation time.

Aberrant expression of Cancer Osaka Thyroid Oncogene mitogen-activated protein kinase kinase kinase 8 (COT) (MAP3K8) is a driver of resistance to B-RAF inhibition. However, the de novo expression and clinical implications of COT in papillary thyroid cancer (PTC) have not been investigated.The aim of this study is to investigate the expression of A-, B-, C-RAF, and COT in PTC (n = 167) and analyze the clinical implications of aberrant expression of these genes.Quantitative polymerase chain reaction (qPCR) and immunohistochemical staining (IHC) were performed on primary thyroid cancers. Expression of COT was compared with clinicopathological characteristics including recurrence-free survival. Datasets from public repository (NCBI) were subjected to Gene Set Enrichment Analysis (GSEA).qPCR data showed that the relative mRNA expression of A-, B-, C-RAF and COT of PTC were higher than normal tissues (all P < 0.01). In addition, the expression of COT mRNA in PTC showed positive correlation with A- (r = 0.4083, P < 0.001), B- (r = 0.2773, P = 0.0003), and C-RAF (r = 0.5954, P < 0.001). The mRNA expressions of A-, B,- and C-RAF were also correlated with each other (all P < 0.001). In IHC, the staining intensities of B-RAF and COT were higher in PTC than in normal tissue (P < 0.001). Interestingly, moderate-to-strong staining intensities of B-RAF and COT were more frequent in B-RAF-positive PTC (P < 0.001, P = 0.013, respectively). In addition, aberrant expression of COT was related to old age at initial diagnosis (P = 0.045) and higher recurrence rate (P = 0.025). In multivariate analysis, tumor recurrence was persistently associated with moderate-to-strong staining of COT after adjusting for age, sex, extrathyroidal extension, multifocality, T-stage, N-stage, TNM stage, and B-RAF mutation (odds ratio, 4.662; 95% confidence interval 1.066 - 21.609; P = 0.045). Moreover, moderate-to-strong COT expression in PTC was associated with shorter recurrence-free survival (mean follow-up duration, 14.2 ± 4.1 years; P = 0.0403). GSEA indicated that gene sets related to B-RAF-RAS (P < 0.0001, false discovery rate [FDR] q-value = 0.000) and thyroid differentiation (P = 0.048, FDR q-value = 0.05) scores were enriched in lower COT expression group and gene sets such as T-cell receptor signaling pathway and Toll-like receptor signaling pathway are coordinately upregulated in higher COT expression group (both, P < 0.0001, FDR q-value = 0.000).Aberrant expression of A-, B-, and C-RAF, and COT is frequent in PTC; increased expression of COT is correlated with recurrence of PTC.

Background: Tumor multifocality is frequently observed in papillary thyroid carcinoma (PTC), but its prognostic value is controversial. We investigated the prognostic significance of multifocality in PTCs larger than 1 cm and papillary thyroid microcarcinomas (PTMC)., Methods: Medical records and pathologic results of 2,309 patients who received thyroidectomy and lymph node dissection for PTC were retrospectively reviewed. We identified 648 patients who had PTC with a primary tumor exceeding 1 cm, and 1,661 patients with PTMC. In each group, we compared patients with unifocal and multifocal disease. Cox regression analyses of disease persistence and recurrence were performed to identify the prognostic significance of multifocality., Results: The mean follow-up period was 5.6 years. In the analyses of PTCs larger than 1 cm, the multifocal group included more extensive thyroid surgeries (p = 0.039), radioactive iodine therapies with higher doses (p < 0.001), and significantly higher rates of disease persistence and recurrence (p = 0.001) compared with the unifocal group. In analogous analyses of patients with PTMC, disease persistence and recurrence did not differ significantly between the unifocal and multifocal groups. Cox regression analyses indicated that multifocality was an independent risk factor for disease persistence and recurrence in patients who had PTC with a tumor exceeding 1 cm, but not in patients with PTMC., Conclusion: Tumor multifocality appears to be an important prognostic factor for PTCs larger than 1 cm, but may have little or no prognostic significance for PTMC.

Background: The present study was designed to investigate the necessity of completion thyroidectomy for patients who underwent thyroid lobectomy for low-risk papillary thyroid microcarcinoma (PTMC) that was later pathologically diagnosed as central lymph node (CLN) metastasis., Methods: Between 1986 and 2001, we assessed 551 patients who underwent thyroidectomy with prophylactic ipsilateral central compartment neck dissection, and 409 patients were followed-up completely. Thyroid lobectomy were performed in 281 and 128 patients, respectively. The patients were divided into two groups according to CLN metastasis. Clinicopathological profiles and follow-up details were investigated by retrospective chart review., Results: The CLN-positive and -negative groups were comprised of 43 (15.2 %) and 238 patients (84.8 %), respectively. The mean ages of the two groups were not significantly different (p > 0.05). The mean tumor size of the CLN-positive group (6.8 mm) was significantly larger than that of the CLN-negative group (5.6 mm; p < 0.05). Microscopic capsular invasion was significantly higher in the CLN-positive group (51.2 vs. 23.9 %; p < 0.05). Overall, 21 patients (7.4 %, 21/281) experienced recurrence. Among these, 2 (4.7 %, 2/43) and 19 (8.0 %, 19/238) were in the CLN-positive and -negative groups, respectively. There was no significant correlation between CLN metastasis and tumor recurrence., Conclusions: Postoperative recurrence was lower in the CLN-positive group, and there was no significant correlation between CLN metastasis and tumor recurrence. Our results suggest that it is not necessary to perform completion thyroidectomy for PTMC patients who have undergone thyroid lobectomy and who have been pathologically diagnosed with CLN metastasis.

Functional chemokine (C-X-C motif) receptor 4 (CXCR4) is well known to be over-expressed in papillary thyroid carcinoma (PTC). The aim of this study was to evaluate whether or not the expression of CXCR4 is different by histological subtypes of PTC and to elucidate the relationship between the expression of CXCR4 and clinicopathologic factors. CXCR4 expression in 127 PTC samples was assessed using immunohistochemical staining. The expression of CXCR4 showed different patterns according to the histological subtype of PTC (p < 0.001). A strong expression of CXCR4 was observed more frequently in the poorly differentiated region of PTC (81.0 %) than in classical PTC (50.0 %). Strong CXCR4 expression was less frequently shown in follicular variant (33.9 %) and in diffuse sclerosing variant (14.3 %) of PTC. CXCR4 expression showed a distinct pattern according to the histological subtype of PTC although not associated with other clinicopathological parameters.

Aims: The objectives of this study were to compare long-term outcomes after total thyroidectomy (TT) or thyroid lobectomy (LT) in a large cohort of patients with papillary thyroid microcarcinoma (PTMC), and to determine whether tumor size (≤0.5 cm vs. >0.5 cm) has a significant impact on the extent of surgery., Methods: We evaluated 2014 patients with PTMC who underwent TT with central compartment node dissection (CCND; n = 1015) or LT with CCND (n = 999) between March 1986 and December 2006 and for whom complete follow-up data were available for at least 5 years (median 11.8 years, range 5-26 years). Using propensity score matching to reduce the impact of treatment selection bias and potential confounding in an observational study, we compared overall survival and disease-free survival in the overall cohort and in patients with tumors ≤0.5 cm and >0.5 cm in size., Results: After adjustment for differences in baseline clinicopathologic risk factors, we observed no significant differences between the LT and the TT groups in the risk of death (hazard ratio for the LT group 1.05, 95% confidence interval [CI] 0.71-1.47, p = 0.890) and locoregional recurrence (hazard ratio for the LT group 3.08 [CI 1.99-8.05], p = 0.194) in the overall matched cohort. Similar results were observed when we compared LT and TT in patients with tumors ≤0.5 cm and >0.5 cm., Conclusions: The long-term rates of death and locoregional recurrence were similar in patients with PTMC who underwent LT with CCND and those who underwent TT with CCND. Therefore, completion thyroidectomy may not be recommended unless recurrence after LT is definitely detected in low-risk PTMC patients, and close follow-up is adequate in these patients. Moreover, tumor size greater than or less than 0.5 cm was not a significant determinant of the extent of surgery in patients with PTMC.

Objectives: Robotic total thyroidectomy (TT) with modified radical neck dissection (MRND) using a gasless transaxillary approach has been reported safe and effective in patients with N1b papillary thyroid carcinoma (PTC), with notable cosmetic benefits when compared with conventional open TT. We have compared oncological outcomes and quality of life (QoL) in PTC patients undergoing robotic TT and MRND and those undergoing conventional open procedures., Materials and Methods: Between March 2010 and July 2011, 128 patients with PTC and lateral neck node metastases underwent TT with MRND, including 62 who underwent robotic and 66 who underwent open TT. We compared oncologic outcomes and safety as well as functional outcomes such as postoperative subjective voice and swallowing difficulties. We also evaluated neck pain, sensory changes, and cosmetic satisfaction after surgery using various QoL symptom scales. Neck and shoulder disability was assessed using arm abduction tests (AAT) and questions from the neck dissection impairment index (NDII)., Results: Although the mean operating time was significantly longer in the robotic (mean, 271.8 ± 50.2 min) than in the open group (mean, 208.9 ± 56.3 min) (P < .0001), postoperative complication rates and oncologic outcomes, including the results of radioactive iodine scans and postoperative serum Tg concentrations, did not differ significantly. Subjective voice outcomes and postoperative AAT and neck dissection impairment index were also similar, but postoperative swallowing difficulties (P = .0041) and sensory changes (P < .0001) were significantly more frequent in the open than in the robotic group. In particular, mean cosmetic satisfaction score was significantly higher in the robotic than in the open group (P < .0001)., Conclusions: Robotic TT with MRND yielded similar oncologic outcomes and safety as conventional open procedures, with similar recovery of neck and shoulder disability. However, the robot technique resulted in better QoL outcomes, including better cosmetic results and reductions in neck sensory changes and swallowing discomfort.

Purpose: To determine differences in ultrasonography (US) features suggesting papillary thyroid carcinoma (PTC) between nodules larger than 10 mm (large lesions) and nodules ≤10 mm in diameter (small lesions)., Methods: We included 1,238 nodules in 1,173 patients that were confirmed through cytology or histopathology between February 2007 and June 2007 in the study. Nodules were divided into large lesions (571 lesions) and small lesions (667 lesions). Sonographic features were defined as composition, echogenicity, margin, calcifications, shape, and vascularity. Logistic regression analyses were performed to determine the odds ratios (OR) of each feature to predict PTC., Results: On multivariate analysis, irregular margin (OR = 37.788, P < 0.001), microcalcifications (OR = 17.799, P < 0.001), microlobulated margin (OR = 10.385, P < 0.001), and no vascularity (OR = 5.975, P < 0.001) were independent factors for PTC in the large lesions and irregular margin (OR = 7.185, P < 0.001), microlobulated margin (OR = 5.952, P < 0.001), microcalcifications (OR = 3.722, P < 0.001), marked hypoechogenicity (OR = 2.873, P = 0.004), and taller than wide shape (OR = 2.698, P < 0.001) were independent factors for PTC in the small lesions., Conclusions: The OR of each US finding for predicting PTC is different between large and small lesions. Therefore, it would be helpful to weight certain US features according to nodule size when reporting thyroid nodules with different risks of PTC.

The study aimed to identify the clinical characteristics of coexisting chronic lymphocytic thyroiditis (CLT) in papillary thyroid carcinoma (PTC) and to evaluate the influence on prognosis. A total of 1,357 patients who underwent thyroid surgery for PTC were included. The clinicopathological characteristics were identified. Patients who underwent total thyroidectomy (n = 597) were studied to evaluate the influence of coexistent CLT on prognosis. Among the total 1,357 patients, 359 (26.5%) had coexistent CLT. In the CLT group, the prevalence of females was higher than in the control group without CLT (P < 0.001). Mean tumor size and mean age in the patients with CLT were smaller than without CLT (P = 0.040, P = 0.047, respectively). Extrathyroidal extension in the patients with CLT was significantly lower than without CLT (P = 0.016). Among the subset of 597 patients, disease-free survival rate in the patients with CLT was significantly higher than without CLT (P = 0.042). However, the multivariate analysis did not reveal a negative association between CLT coexistence and recurrence. Patients with CLT display a greater female preponderance, smaller size, younger and lower extrathyroidal extension. CLT is not a significant independent negative predictive factor for recurrence, although presence of CLT indicates a reduced risk of recurrence.

The present study was designed to determine the impact of secondary review of thyroid fine-needle aspiration (FNA) biopsy on surgical management. A retrospective review of patients referred to our institution with a thyroid FNA biopsy was conducted. Cytologic diagnoses from the report at our center and the referring institution were re-categorized by the Bethesda System for Reporting Thyroid Cytopathology. The rate of diagnostic disagreement was evaluated between Primary Diagnosis (PD) and Second Opinion Diagnosis (SOD), and the clinicopathologic correlations and the number of cases that prompted changes in treatment as a result of diagnostic disagreement were analyzed. 1499 patients meeting our study criteria were enrolled in this study. Diagnostic disagreement comprised 394 cases (26.3%). In the case of diagnostic disagreement, SOD was supported on clinicopathologic follow-up in 271 cases (68.8%), of which a change in management was made in 54 (13.7%) cases, and PD was supported in 93 (23.6%) cases, of which a change in management was made in 13 (3.3%) cases. By the second opinion, 65 (4.5%) patients received proper management, and 14 (1.0%) patients received superfluous management. Wide use of secondary cytopathologic review of thyroid FNA specimens from referring institutions was recommended.

Background: This study was designed to evaluate the performance of ultrasonography (US) for the preoperative staging of papillary thyroid carcinoma (PTC) in a large series according to the TNM classification., Methods: Preoperative US was performed for the evaluation of primary tumors and lymph node metastasis in 722 consecutive patients with cytologically proven PTC. Three experienced radiologists prospectively determined T and N categories of PTC. N categorization was based on compartments, including left and right lateral compartments (levels II-V) and central compartment (level VI). All patients underwent surgery and central compartment dissection. Lateral compartment dissection was selectively performed. We assessed the diagnostic performance of preoperative US for staging of PTC on the basis of pathologic findings of surgical specimens. Subgroup analysis according to suspicion of diffuse thyroid disease (DTD) on US was performed to compare US accuracies for N categorization., Results: US predicted 61.7% (142/230) of patients with multifocal PTC and 67.1% (100/149) of patients with bilateral malignancy. Overall accuracy of US for T categorization was 69.7% (503/722) and that of US for N categorization was 59% (426/722). Accuracies of sonographic categorization for N0, N1a, and N1b were 66% (276/418), 33.3% (70/210), and 85.1% (80/94), respectively. Overall US accuracy for prediction of an N category was significantly lower in patients with US-indicated DTD (51.1%, 67/131) than it was in patients without DTD (60.7%, 359/591; P = 0.043)., Conclusions: Preoperative US is a feasible technique for the preoperative staging of PTC and is helpful for the detection of lateral compartment metastasis. Presence of DTD can affect the staging of lymph node metastasis.

Background: Robotic thyroidectomy (RT) has recently emerged as a viable approach to thyroid surgery, resulting in better functional and cosmetic outcomes than afforded by open thyroidectomy (OT). The present multicenter study assessed the perioperative outcomes of RT and compared physician perspectives on the musculoskeletal ergonomic parameters associated with OT, endoscopic thyroidectomy (ET), and RT., Materials and Methods: We reviewed the medical records of 2014 consecutive patients who underwent RT, conducted by 7 surgeons, at 4 centers between October 2007 and June 2010. Patient characteristics, perioperative clinical results, complications, and pathologic outcomes were analyzed. Moreover, surgeons were surveyed to gather data on musculoskeletal discomfort experienced during OT, ET, and RT., Results: Of the 2014 patients, 740 underwent total and 1274 subtotal thyroidectomy. Mean tumor diameter was 0.8 cm, and the mean number of retrieved central lymph nodes was 4.5 ± 3.9 (range 0-28). The rates of permanent recurrent laryngeal nerve injury and permanent hypocalcemia were 0.4 and 0.05%, respectively. Neck and/or back pain after OT, ET, and RT was experienced by 100, 85.7, and 28.6% of surgeons, respectively. When surgeons ranked the operative approaches in decreasing order of associated pain, 57.1% indicated ET > OT > RT, 28.6% selected OT > ET > RT, and 14.3% responded ET > RT > OT., Conclusion: RT is a feasible and safe procedure that may facilitate radical cervical lymph node dissection. Moreover, for surgeons, the RT resulted in less musculoskeletal discomfort than did OT or ET. A larger prospective study, with a longer follow-up, is needed to determine whether RT offers real benefits for both patients and surgeons.

Background: The clinical impact of minimal extrathyroidal extension (ETE) in patients with conventional papillary thyroid microcarcinoma (PTMC) is still controversial. The clinicopathologic characteristics of patients with or without minimal ETE or recurrence and the clinical impact of minimal ETE were investigated., Methods: This study included 288 patients with conventional PTMC (mean age, 46.6 years; 262 female and 26 male subjects) and more than 5 years of follow-up. Patients were divided into two groups according to ETE and recurrence, and clinicopathologic characteristics between two groups were investigated. Disease-free survival was calculated to compare the clinical impact of minimal ETE between patients with and without ETE., Results: Mean size (6.9 mm) of PTMCs in patients with minimal ETE (n = 89) was significantly larger than that in those (5.8 mm) without (n = 199) (P < 0.001). Tumor size [odds ratio (OR) = 1.185; 95% confidence interval (CI) 1.052-1.334], central lymph node (LN) metastasis at diagnosis (OR 2.105; 95% CI 1.182-3.750), and not well-defined margin on ultrasound (OR 3.808; 95% CI 1.055-13.736) were significantly associated with minimal ETE. Twelve patients (4.2%) had recurrence. No clinicopathologic factor was associated with recurrence. Disease-free survival was not significantly different between patients with and without minimal ETE (P = 0.671)., Conclusions: Minimal ETE was statistically significantly associated with tumor size, central LN metastasis, and not well-defined margin on ultrasound. Minimal ETE had no impact on recurrence in patients with conventional PTMC.

Background: Papillary thyroid carcinoma (PTC) is the most frequent carcinoma of the thyroid gland and has a relatively good prognosis. However, it is important to identify PTC characteristics that indicate high risk for recurrence and metastasis. To date, overexpression of the membrane mucin, MUC1, has been investigated as a key molecular event in the pathogenesis of aggressive PTC. However, other membrane-associated mucins, matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-13 (TIMP-3), have not been studied yet. The aim of this study was to evaluate the expression levels of MUC4, MUC15, MMP-13, and TIMP-3 and their prognostic significance in PTC., Methods: We analyzed MUC4, MUC15, MMP-13, and TIMP-3 expression in 10 PTC and 10 normal thyroid tissue samples using real-time reverse transcription-polymerase chain reaction. Tissue array blocks were obtained from 98 PTC cases. Tumor regions and nontumor regions were analyzed in tissue array blocks and immunohistochemistry studies were conducted using sectioned slides. Semiquantitative scores were correlated with clinicopathological factors of 98 PTC patients., Results: MUC4- and MUC15-specific mRNA was increased by 78-fold and 4.75-fold, respectively, in PTC samples compared with normal thyroid tissues. MMP-13 and TIMP-3 gene expression levels were decreased by approximately 0.39-fold and 0.53-fold, respectively. By immunohistochemistry, MUC4 and MUC15 expression levels were increased in PTC samples compared with normal thyroid tissues (p < 0.001). MMP-13 and TIMP-3 expression levels were decreased in PTC samples compared with normal thyroid tissues (p < 0.001). High MUC4 scores were significantly correlated with small tumor size and papillary thyroid microcarcinoma subtype. High MUC15 scores were significantly correlated with age (≥45 years), distant metastasis, and multifocality., Conclusions: MUC4 and MUC15 were overexpressed in PTC, and high MUC15 expression was associated with high malignant potential. MUC15 may serve as a prognostic marker and potential novel therapeutic target in PTC.

Background: We investigated the diagnostic value of the BRAF(V600E) mutation of thyroid nodules according to ultrasonography (US) features and the time of BRAF(V600E) mutation analysis., Methods: A total of 304 nodules in 295 patients (mean age, 49.4 years) were included. Thyroid nodules were classified as suspicious or probably benign on US. Group 1 (n = 168) included nodules with BRAF(V600E) mutation analysis at the time of the initial US-guided fine needle aspiration biopsy (US-FNAB) and group 2 (n = 136) included nodules with analysis at the time of the repeat US-FNAB. The frequency of malignancy and the BRAF(V600E) mutation were compared between suspicious and probably benign nodules on US and between groups 1 and 2., Results: Of 304 nodules, 113 were malignant and 59 (52.2%) had the BRAF(V600E) mutation. Also, 58 of 196 nodules suspicious on US (29.6%) had the BRAF(V600E) mutation, whereas 1 of 108 (0.9%) probably benign nodules had the BRAF(V600E) mutation (P value <.0001). The BRAF(V600E) mutation was more frequently found in nodules suspicious on US than those probably benign in both groups 1 and 2 (P value <.0001 and .0058, respectively). Preoperative detection of the BRAF(V600E) mutation led surgeons to perform surgery in 5.8% of 103 nodules with benign and nondiagnostic results on cytology in group 1 and 1% of 98 nodules in group 2 without treatment delay., Conclusions: The BRAF(V600E) mutation analysis was a useful adjunctive diagnostic tool, especially in nodules suspicious on US, and was more effective if performed at the time of the initial US-FNAB.

Objectives: Robotic thyroidectomy and lymph node dissection is rapidly emerging as an alternative to conventional endoscopic thyroidectomy for thyroid carcinoma. Robot techniques incorporate the advantages of endoscopic procedures while overcoming some of the problems. We present the largest multi-institution clinical study of robotic thyroidectomy for thyroid carcinomas. The robotic thyroidectomy involved gasless transaxillary approach using the da Vinci surgical robot system., Methods: We reviewed a database of 1,043 consecutive patients with low-risk differentiated thyroid carcinoma who underwent robotic thyroidectomy between October 2007 and August 2009. Operations were performed by five surgeons at four academic centers. We analyzed perioperative, clinical, and pathological data., Results: The study involved 71 men and 972 women, with a mean age of 39 (range, 15-70) years. All operations were performed successfully without any need for conventional open or endoscopic conversion. There were 366 total thyroidectomies and 677 subtotal thyroidectomies with cervical lymph node dissection. The mean overall operation time and console time were 132.4 and 63.9 min, respectively. There were ten (1%) major postoperative morbidities. The mean tumor size was 0.8 (range, 0.1-6.0) cm, and the mean number of retrieved central lymph nodes was 5.1 ± 3.8 (range, 0-26). The mean postoperative hospital stay was 2.9 (range, 1-8) days., Conclusions: Robotic thyroidectomy using gasless transaxillary method was feasible, safe, and provided good outcomes for patients with differentiated thyroid carcinoma. Robotic technology overcame some technical limitations associated with conventional endoscopy.

Purpose: The learning curve for robotic thyroidectomy with central compartment node dissection (CCND) has not been established. We examined the effect of experience of robotic thyroidectomy on a range of perioperative parameters in order to determine the learning curve. The learner surgeon outcomes were compared with those of an experienced surgeon., Methods: We conducted a prospective, controlled, multicenter study involving four endocrine surgeons at three academic centers. Patients underwent robotic total or subtotal thyroidectomy with CCND between September 2008 and October 2009. One surgeon was experienced in the technique (experienced surgeon, ES), while the other three surgeons had endoscopic thyroid surgery experience but no experience performing the robotic procedure (nonrobotic thyroid surgery experienced surgeon, NS). Outcome measures were demographic data, operative time, blood loss, hospital stay, pathologic results, and postoperative complications., Results: A total of 644 total or subtotal robotic thyroidectomies with CCND were performed: 377 (58.7%) by NSs and 267 (41.5%) by the ES. Mean operative time was longer and the complication rate was higher for the NS patient group compared with the ES patient group (P < 0.001 for each). The operative times and complications rates for the NS group were similar to those of the ES group once the NSs had performed 50 cases for total thyroidectomies or 40 cases for subtotal thyroidectomies., Conclusion: The learning curve duration for robotic thyroidectomy with CCND using gasless transaxillary approach for experienced endoscopic thyroidectomy surgeons was 50 cases for total thyroidectomy and 40 cases for subtotal thyroidectomy.

Although the presence of aggressive angioinvasion is not a contraindication for surgical treatment of well-differentiated thyroid cancer, surgical resection and reconstruction of the major arteries in the neck and mediastinum using a synthetic graft is rarely performed. We present our experience of resection and reconstruction of the major arteries in the neck for the treatment of locally advanced thyroid cancer. A 66-year-old woman presented with locally advanced thyroid cancer with invasion of the right internal jugular vein and vagus nerve. The cancer mass encased the junction of the right common carotid artery, the subclavian artery, and the brachiocephalic trunk. After en-bloc resection of the tumor, the arteries were reconstructed using a Y-shaped synthetic graft between the common carotid artery, aorta, and the subclavian artery. Postoperatively, there was no evidence of cerebral ischemia and the patient made a rapid recovery without complications. An aggressive surgical approach is appropriate for grossly invasive thyroid cancer to decrease the risk of local recurrence and increase survival. Surgical resection and reconstruction of the major arteries in the neck and chest using a synthetic graft can be an acceptable therapeutic option for locally advanced thyroid cancer.

Background: The purpose of the present study was to evaluate the clinicopathologic characteristics and short-term outcomes of papillary thyroid carcinomas (PTC) located in the isthmus compared to tumors located in other thyroid regions, and to use those findings to establish a surgical strategy for treating these tumors., Patients and Methods: Thyroidectomy was performed in 1,973 thyroid cancer patients in our hospital between January 2006 and December 2007. The patients were analyzed in two groups; group I, patients with tumors located in the isthmus (n = 181) and group II, patients with tumors located in other thyroid regions (n = 1,792). The clinicopathologic characteristics and short-term outcomes were compared between the two groups., Results: The study groups were similar in terms of age and gender ratio. For groups I and II, respectively, the mean primary tumor size was 1.02 cm and 1.13 cm (p = 0.017), capsular invasion frequency was 70.2 and 60.8% (p = 0.008), and multifocality frequency was 48.6 and 39.8% (p = 0.006). In addition, central node involvement was 40.3 and 42.1% (p = 0.350), and lateral node involvement was 9.4 and 18.2% (p = 0.001). At the time of postoperative iodine-131 remnant ablation, 34.3% of group I patients and 38.0% of group II patients showed undetectable serum thyroglobulin concentrations. There were no significant differences in surgical complications between the two groups., Conclusions: Papillary thyroid carcinomas located in the isthmus was more likely to be associated with multiple foci in bilateral lobes and higher rates of capsular invasions than tumors in other thyroid regions. These findings indicate that total thyroidectomy is an appropriate initial surgical procedure for the isthmic PTC.

Purpose: To evaluate the association of known prognostic factors with the BRAF(V600E) mutation and its association with ultrasonographic (US) features in Korean patients with papillary thyroid microcarcinoma (PTMC)., Materials and Methods: This retrospective study was institutional review board approved; informed consent was not required from patients. From July 2008 to November 2008, 339 consecutive patients underwent surgery for PTMC. US-guided fine-needle aspiration biopsy was performed to evaluate BRAF status in thyroid nodules before surgery. Logistic regression analysis was performed to assess the association between BRAF status, determined by using clinicopathologic factors, and several US features., Results: Univariate analysis revealed an association between the BRAF(V600E) mutation and both tumor size and extracapsular invasion. Tumor size, extracapsular invasion, and high TNM stage (III and IV) were significantly associated with BRAF(V600E) in multivariate analysis. BRAF(V600E) was not significantly associated with any US features., Conclusion: The BRAF(V600E) mutation can be used as a potential prognostic factor in PTMC patients in a BRAF(V600E)-prevalent area. Future studies will be needed to determine how this information can be used to alter patient care.

Background: The aim of this study was to evaluate and compare the early surgical outcomes of endoscopic and conventional open thyroidectomies in patients with papillary thyroid microcarcinoma (PTMC)., Methods: Between September 2005 and December 2007, 499 patients with PTMC were enrolled. 275 patients underwent gasless endoscopic thyroidectomy via the axillary route (endo group), and 224 patients underwent conventional open thyroidectomy (open group). We analyzed the patient's clinico-pathologic characteristics and surgical completeness between the two groups., Results: The endo group was younger than the open group. The open group underwent more extensive surgery than the endo group. The operative time was longer in the endo group than the open group (138.5 +/- 49.0 min vs. 105.5 +/- 41.6 min; P < 0.0001), and a lesser number of lymph nodes were retrieved in the endo group compared to the open group (5.05 +/- 2.94 vs. 5.96 +/- 4.50, P = 0.007). We experienced complications in the endo group, such as transient hypocalcemia, transient RLN palsies, tracheal injuries, and esophageal injuries. There was no abnormal uptake on RAI scans in the two groups. From among patients who had undergone total thyroidectomy, all patients in the endo group had <1 ng/ml of serum Tg post-operatively; the seven patients in the open group had >1 ng/ml of serum Tg post-operatively. Tumor recurrence was detected in the open group only (n = 6). Also we checked the post-operative Tg in patients who had undergone lobectomy in the two groups, and found that there were no statistical differences in the two groups., Conclusions: According to our experience, gasless endoscopic thyroidectomy using a trans-axillary approach is a safe and feasible alternative to conventional open thyroidectomy in selected patients with PTMC.

Objectives: The optimal extent of surgery and postoperative management of patients with well differentiated thyroid carcinoma (WDTC) vary among countries and institutions. We assessed the practical management of WDTC in Korea by questionnaire and compared these results with those obtained in similar surveys of members of the Japanese Society of Thyroid Surgery (JSTS) and the International Association of Endocrine Surgeons (IAES)., Materials and Methods: Questionnaires were sent by mail or e-mail to 266 members of the Korean Association of Endocrine Surgeons (KAES). Ninety members (33.8%) completed the questionnaire; their responses were compared with those of the JSTS and IAES surveys., Results: Total thyroidectomy was more prevalent in the KAES and IAES than in the JSTS, irrespective of tumor size in the low-risk group. Patients with papillary microcarcinoma were more likely to undergo aggressive central compartment node dissection in the KAES than in the IAES or JSTS. Thyroid stimulating hormone suppression therapy was administered to a higher proportion of patients and for longer times in the KAES and IAES than in the JSTS. Postoperative radioactive iodine treatment was more prevalent in the KAES than in the JSTS. There were no differences between the KAES and the JSTS in the treatment of patients with locally advanced thyroid carcinoma. External irradiation and radioactive iodine treatment for recurrent papillary thyroid carcinoma were favored more by the KAES than the IAES and JSTS., Conclusions: The actual practices of members of the KAES were almost similar to those of the IAES, but differed from those in Japan in some aspects. In general, however, members of the KAES favored more aggressive treatment of WDTC than did physicians in other countries.

Objective: Percutaneous ethanol injection therapy (PEIT) has been used to treat various human neoplasms. We evaluated the local therapeutic effect of PEIT in recurrent thyroid cancers., Design: From October 2002 to September 2005, we performed ultrasound-guided PEIT on 24 recurrent lesions (eight in thyroid beds and 16 in neck nodes) of 16 papillary thyroid carcinoma patients. Ethanol was injected at 3-month intervals under sonographic guidance., Main Outcome: All patients tolerated PEIT well with only mild local pain, although one patient complained of transient hoarseness after the procedure. The median diameter of lesions was significantly reduced, from 9.9 mm (range, 5.5-25.0 mm) to 5.3 mm (range, 0.0-17.0 mm) by PEIT. Four recurrent lesions disappeared sonographically., Conclusion: PEIT may be an alternative treatment option for locally recurrent thyroid carcinomas in properly selected patients. However, a prospective, long-term follow-up study is necessary to determine the effect of PEIT on patient survival and tumor recurrence.

Purpose: To determine the role of adjuvant external-beam radiotherapy (EBRT) in the management of patients with well-differentiated thyroid cancer invading the trachea., Methods and Materials: Of 1,098 thyroid cancer patients, 68 (6%) were found to have tracheal invasion, and they all received "shave" excision of the tracheal cartilage. Among them, 12 patients had no postoperative residuum, 43 patients had microscopic residuum, and 13 patients had macroscopic residuum. All patients were divided into two groups according to treatment modality with or without EBRT; (1) the control group (n = 43) and (2) the EBRT group (n = 25)., Results: The locoregional recurrence rate for EBRT patients was much lower than that of control patients (51% for the control group vs. 8% for the EBRT group) (p < 0.01). The 10-year local progression-free survival rate for the EBRT group was significantly better than that of the control group (89% in the EBRT group vs. 38% in the control group) (log-rank, p < 0.01). The use of adjuvant EBRT after conservative surgery was an independent prognostic factor in univariate and multivariate analyses., Conclusions: External-beam radiotherapy was found to be effective, particularly in patients with thyroid cancer invading the trachea with microscopic or gross residuum after conservative surgery.