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Background: The increased usage and adaptation of molecular testing of thyroid fine needle aspirations (FNA) has expanded the variety and number of gene fusions identified. While the identified number of molecular alterations is increasing, the definitive association between preoperative molecular analysis and phenotype has yet to be established. The aim of this study was to examine Thyroid adenoma-associated (THADA)-IGF2BP3 molecular fusions with FNA categorization, surgical pathology diagnosis, and other molecular alterations detected by ThyroSeq Genomic Classifier testing., Methods: FNA cytology samples of thyroid nodules from 04/2017 to 01/2023 with the diagnosis of atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS; Bethesda III) or follicular neoplasm suspicious for follicular neoplasm (FN/SFN; Bethesda IV) with associated ThyroSeqV3 testing were reviewed. Parameters including patient demographics, FNA diagnosis, ThyroSeq V3 results, and surgical pathology follow up were examined., Results: 87 out of 249 (35%) FNA specimens of thyroid nodules displayed molecular alterations. 64 cases (74%) had a cytology diagnosis of AUS and 23 (26%) had FN. RAS mutation was observed in 48 cases. On surgical follow-up, 17 (35%) cases showed non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), while 14 (29%) patients had a malignant diagnosis. THADA-IGF2BP3 fusions were seen in 8 cases, all with NIFTP on surgical pathology follow-up (100%)., Conclusions: Analysis of THADA-IGF2BP3 fusion, in our institutional series, shows close association with NIFTP cases. THADA-IGF2BP3 fusion, which seems to be a favorable prognostic indicator in general, may serve as a molecular marker for non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)., (© 2024 Wiley Periodicals LLC.)

Objective: Previous reports suggest that a high body mass index (BMI) increases the risk of thyroid carcinoma. However, it remains unclear whether a high BMI is associated with the risk of the BRAFV600E mutation. We aimed to assess whether a high BMI is associated with an increased risk of the BRAFV600E mutation., Design and Methods: We screened 6558 PTC patients who had undergone BRAFV600E mutation testing between January 2009 and December 2017. After exclusion, 6438 PTC patients were enrolled. We used logistic regression, and restricted cubic spline plots of the adjusted odds ratios (ORs) were illustrated to model the relationship between BMI and the BRAFV600E mutation., Results: Of the 6438 patients, 5102 (79.2%) had the BRAFV600E mutation, and 4954 (76.9%) were female. The median BMI was 23.8 (21.6-26.2) kg/m2. The primary tumor size was ≤1 cm in 4226 patients (65.6%) and >1 cm in 2212 patients (34.4%). The BRAFV600E mutation was significantly associated with high BMI only in patients with a primary tumor size >1 cm (OR: 1.034; 95% CI: 1.003-1.065; P = 0.029), whereas no clear association was found in patients with a primary tumor size ≤1 cm (OR: 1.007; 95% CI: 0.984-1.030; P = 0.570). Gender was not a significant factor in either group., Conclusions: Our study found that a higher BMI was positively associated with the BRAFV600E mutation in patients with a primary tumor size >1 cm. These results suggest that the association between BMI and the BRAFV600E mutation status differs depending on primary tumor size., Significance Statement: Obesity has been suggested as a potential risk factor for thyroid carcinoma. The aim of this study was to assess the association between BMI and the BRAFV600E mutation. In this study, the BRAFV600E mutation was significantly associated with a high BMI only in a primary tumor size >1 cm (OR: 1.034; P = 0.029). No clear association was found in patients with a primary tumor size ≤1 cm (OR: 1.007; P = 0.570). The association between BMI and the BRAFV600E mutation status differs depending on the primary tumor size.

Purpose: BRAF mutations are detected in 30%-80% of papillary thyroid cancer (PTC) cases. DaBRAFenib and trametinib showed promising antitumor activity in patients with BRAFV600E-mutated metastatic melanoma and non-small cell lung cancer. This study aimed to evaluate the efficacy and safety of daBRAFenib and trametinib in patients with metastatic BRAFV600E-mutated thyroid cancer., Materials and Methods: This was a retrospective study to evaluate the efficacy of daBRAFenib and trametinib in patients with metastatic BRAFV600E-mutated PTC. The patients received daBRAFenib 150 mg twice daily and trametinib 2 mg once daily at the Samsung Medical Center. This study evaluated the progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) overall survival (OS), and safety of daBRAFenib and trametinib., Results: Between December 2019 and January 2022, 27 PTC patients including eight patients with poorly differentiated or anaplastic transformation, received daBRAFenib and trametinib. The median age was 73.0 years, and the median follow-up period was 19.8 months. The majority (81.5%) had undergone thyroidectomy, while 8 patients had received prior systemic treatments. ORR was 73.1%, with 19 partial responses, and DCR was 92.3%. Median PFS was 21.7 months, and median OS was 21.7 months. Treatment-related adverse events included generalized weakness (29.6%), fever (25.9%), and gastrointestinal problems (22.2%). Dose reduction due to adverse events was required in 81.5% of the patients., Conclusion: DaBRAFenib and trametinib demonstrated a high ORR with promising PFS; however, most patients with BRAFV600E-mutated metastatic PTC required a dose reduction.

Backgruound: The adequate dose of levothyroxine (LT4) for patients who have undergone total thyroidectomy (TT) for differentiated thyroid cancer (DTC) is uncertain. We evaluated the LT4 dose required to achieve mild thyroid-stimulating hormone (TSH) suppression in DTC patients after TT., Methods: The electronic medical records of patients who underwent TT for DTC and received mild TSH suppression therapy were reviewed. Linear regression analysis was performed to evaluate the association between LT4 dose (μg/kg) and an ordinal group divided by body mass index (BMI). We also evaluated the trend in LT4 doses among groups divided by BMI and age., Results: In total, 123 patients achieved mild TSH suppression (0.1 to 0.5 mIU/L). The BMI variable was divided into three categories: <23 kg/m2 (n=46), ≥23 and <25 kg/m2 (n=30), and ≥25 kg/m2 (n=47). In the linear regression analysis, BMI was negatively associated with the LT4 dose after adjusting for age and sex (P<0.001). The LT4 doses required to achieve mild TSH suppression based on the BMI categories were 1.86, 1.71, and 1.71 μg/kg, respectively (P for trend <0.001). Further analysis with groups divided by age and BMI revealed that a higher BMI was related to a lower LT4 dose, especially in younger patients aged 20 to 39 (P for trend=0.011)., Conclusion: The study results suggest an appropriate LT4 dose for mild TSH suppression after TT based on body weight in patients with DTC. Considering body weight, BMI, and age in estimating LT4 doses might help to achieve the target TSH level promptly.

Telomerase reverse transcriptase (TERT) promoter mutations are associated with tumor aggressiveness. This study aimed to demonstrate the ultrasonographic (US) features of TERT promoter-mutated follicular thyroid cancer (FTC) and evaluate their predictive performance. A total of 63 patients with surgically confirmed FTC between August 1995 and April 2021 were included. All data were available for analysis of preoperative US findings and TERT promoter mutation results. Genomic DNA was extracted from the archived surgical specimens to identify TERT promoter mutations. Logistic regression analysis was performed to compare US findings between TERT promoter-mutated and wild-type FTCs. Of the 63 patients with FTC, 10 (15.9%) had TERT promoter mutations. TERT promoter-mutated FTCs demonstrated significantly different US suspicion categories compared to wild-type FTCs (Ps = 0.0054 for K-TIRADS and 0.0208 for ACR-TIRADS), with a trend toward an increasing prevalence of the high suspicion category (40.0% for both K-TIRADS and ACR-TIRADS; Ps for trend = 0.0030 for K-TIRADS and 0.0032 for ACR-TIRADS). Microlobulated margins and punctate echogenic foci were independent risk factors associated with TERT promoter mutation in FTC (odds ratio = 9.693, 95% confidence interval = 1.666-56.401, p = 0.0115 for margins; odds ratio = 8.033, 95% confidence interval = 1.424-45.309, p = 0.0182 for punctate echogenic foci). There were no significant differences in the composition and echogenicity of the TERT promoter-mutated and wild-type FTCs. TERT promoter-mutated FTCs were categorized more frequently as high suspicion by the K-TIRADS and ACR-TIRADS. Based on US findings, the independent risk factors for TERT promoter mutations in FTC are microlobulated margins and punctate echogenic foci., (© 2024. The Author(s).)

Background: The recurrence of thyroid cancer poses challenges compounded by postoperative fibrosis and anatomic changes. By overcoming the limitations of current localizing dye techniques, indocyanine green-macroaggregated albumin-hyaluronic acid (ICG-MAA-HA) mixture dye promises improved localization. This study aimed to evaluate the efficacy and safety of the dye for recurrent thyroid cancer., Methods: The nine patients in this study underwent surgery and postoperative ultrasonography. The dye was injected into recurrent lesions in all the patients preoperatively. During surgery, the lesions were confirmed with an imaging system before and after excision. If the lesion was unidentifiable with the naked eye, surgical excision was performed under the corresponding fluorescent guide. Side effects related to the dye injection and completeness of the surgery were evaluated., Results: No side effects such as bleeding, skin tattooing, or pain during or after the dye injection were reported, and no discoloration occurred that interfered with the surgical field of view during surgery. In three cases (33.3 %), because it was difficult to localize metastatic lesions with the naked eye, the operation was successfully completed using an imaging system. The completeness of the surgical resection was confirmed by ultrasonography after an average of 5 months postoperatively., Conclusion: The study found that ICG-MAA-HA dye effectively located metastatic and recurrent thyroid cancer and had favorable results in terms of minimal procedural side effects and potential for assisting the surgeon. A large-scale multi-institutional study is necessary to prove the clinical significance regarding patient survival and disease control., (© 2024. Society of Surgical Oncology.)

Purpose: Papillary thyroid microcarcinoma (PTMC) has an excellent prognosis; however, some PTMCs exhibit poor outcomes. Cancer-specific death from PTMC has been rarely reported, so we aimed to evaluate mortality rates and causes of death in patients who died with PTMC., Methods: We retrospectively reviewed 8969 PTMC patients treated at Samsung Medical Center from 1994 to 2017. Mortality rate and causes of death in PTMC patients were evaluated and compared with those of 7873 patients with papillary thyroid carcinoma (PTC) > 1 cm. In addition, we reviewed previous publications reporting cancer-specific deaths from PTMC., Results: Among the 8969 PTMC patients, 107 (1.2%) patients died. Only two (0.02%) patients have died of PTMC, which was less than the cancer-specific deaths from PTC > 1 cm (0.71%). Among the deceased PTMC patients, 63 (58.9%) died of other malignancies, three (2.8%) died of cardiovascular diseases, and five (4.7%) died of other diseases. Compared with PTC > 1 cm, cancer-specific deaths was less (1.9% vs. 15.1%, P < 0.001), and deaths from other malignancies were higher in deceased PTMC patients (58.9% vs. 30.5%, P < 0.001). According to 18 studies, PTMC-specific mortality rates ranged from 0.05% to 14.3%, and 336 cancer-specific deaths (0.43%) occurred among 78,770 PTMC patients., Conclusion: The cancer-specific mortality rate of PTMC patients was extremely low (0.02%). More than half of deceased PTMC patients died of other malignancies, which was significantly more than those with PTC > 1 cm. These results support that active surveillance can be selected as a therapeutic option for PTMC., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To investigate the association of ultrasound (US) features of follicular thyroid carcinoma (FTC) with tumor invasiveness and prognosis based on the World Health Organization (WHO) classification and telomerase reverse transcriptase (TERT) promoter mutations., Materials and Methods: This retrospective study included 54 surgically confirmed FTC patients with US images and TERT promoter mutations (41 females and 13 males; median age [interquartile range], 40 years [30-51 years]). The WHO classification consisted of minimally invasive (MI), encapsulated angioinvasive (EA), and widely invasive (WI) FTCs. Alternative classifications included Group 1 (MI-FTC and EA-FTC with wild type TERT), Group 2 (WI-FTC with wild type TERT), and Group 3 (EA-FTC and WI-FTC with mutant TERT). Each nodule was categorized according to the US patterns of the Korean Thyroid Imaging Reporting and Data System (K-TIRADS) and American College of Radiology-TIRADS (ACR-TIRADS). The Jonckheere-Terpstra and Cochran-Armitage tests were used for statistical analysis., Results: Among 54 patients, 29 (53.7%) had MI-FTC, 16 (29.6%) had EA-FTC, and nine (16.7%) had WI-FTC. In both the classifications, lobulation, irregular margins, and final assessment categories showed significant differences (all Ps ≤ 0.04). Furthermore, the incidences of lobulation, irregular margin, and high suspicion category tended to increase with increasing tumor invasiveness and worse prognosis (all Ps for trend ≤ 0.006). In the WHO groups, hypoechogenicity differed significantly among the groups ( P = 0.01) and tended to increase in proportion as tumor invasiveness increased ( P for trend = 0.02). In the alternative group, punctate echogenic foci were associated with prognosis ( P = 0.03, P for trend = 0.03)., Conclusion: Increasing tumor invasiveness and worsening prognosis in FTC based on the WHO classification and TERT promoter mutation results were positively correlated with US features that indicate malignant probability according to both K-TIRADS and ACR-TIRADS., Competing Interests: Jung Hee Shin, the editor board member of the Korean Journal of Radiology, was not involved in the editorial evaluation or decision to publish this article. All authors have declared no conflicts of interest., (Copyright © 2024 The Korean Society of Radiology.)

Background: Age at diagnosis (AAD) and telomerase reverse transcriptase (TERT) promoter mutations are prognostic factors in differentiated thyroid carcinoma (DTC), and the prevalence of the mutations increases with AAD. Considering this correlation, we investigated whether an interaction between AAD and the mutations is present and whether the mutation mediates the effect of AAD on the mortality rate in DTC., Methods: The study included 393 patients with DTC who were followed-up after thyroidectomy at a single medical center in Korea from 1994 to 2004. Multivariable Cox regression was used to investigate the interaction of AAD and TERT promoter mutation. Mediation analysis was conducted using a regression-based causal mediation model., Results: The age-associated mortality rate increased progressively in all DTC patients and wild-type TERT group (WT-TERT) with a linear trend (p < 0.001) contrary to mutant TERT group (M-TERT) (p = 0.301). Kaplan-Meier curves declined progressively with increasing AAD in the entire group, but the change was without significance in M-TERT. The effect of AAD on mortality was not significant (adjusted HR: 1.07, 95% CI 0.38-3.05) in M-TERT. An interaction between AAD and TERT promoter mutation (p = 0.005) was found in a multivariable Cox regression. TERT promoter mutations mediated the effect of AAD on the mortality rate by 36% in DTC in a mediation analysis., Conclusions: Considering the mediation of TERT promoter mutation on the effect of AAD on mortality, inclusion of TERT promoter mutation in a stage classification to achieve further individualized prediction in DTC is necessary., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Heo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: To better understand the molecular alterations associated with Hurthle cell lesions of the thyroid, we retrospectively reviewed the association of clonal DNA copy number alterations (CNAs) with fine needle aspiration (FNA) cytomorphology and surgical follow-up., Methods: Hurthle cell type (HCT) and non-Hurthle cell type (NHCT) thyroid FNAs that were classified according to the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) as atypia of undetermined significance (AUS) and suspicious for a follicular neoplasm (SFN) with corresponding molecular testing performed by ThyroSeq v3 genomic classifier were compared to surgical follow-up., Results: A total of 54 thyroid FNA cases were identified, distributed among the following categories: AUS-HCT (n = 15, 27.8%), SFN-HCT (n = 11, 20.4%), AUS-NHCT (n = 19, 35.2%), and SFN-NHCT (n = 9, 16.6%). The lesions classified as AUS-HCT and SFN-HCT showed a higher prevalence of CNAs (n = 10/26; 38.5%) compared to their NHCT counterparts (n = 3/28; 10.7%) (p < .03). Of the 42 patients (77.8%) with surgical follow-up, CNAs were more often seen in benign (n = 10/26, 38.5%) than malignant conditions (n = 1/16, 6.3%) (p < .03). CNAs were encountered in more lesions with Hurthle cell features on histologic examination (n = 8/14, 57.1%) than those without (n = 3/28, 10.7%) (p < .002). The presence of CNAs alone was seen only in benign adenomas and more commonly with Hurthle cell features (n = 5/7, 71.4%)., Conclusion: In this study, CNAs were associated with Hurthle cell morphology on thyroid FNA and benign adenomas upon surgical follow-up. Therefore, if the only finding of a positive ThyroSeq v3 GC result is a CNA, conservative management can be considered if clinically indicated., (© 2023 Wiley Periodicals LLC.)

Current guidelines recommend total thyroidectomy with central lymph node dissection (CND) for patients with medullary thyroid carcinoma (MTC). This study aimed to identify low-risk MTC patients who may be candidates for lobectomy. We retrospectively reviewed MTC patients who underwent primary surgery at a tertiary referral center from 1998 to 2019. Eighty-five MTC patients were enrolled, excluding patients with primary tumor size > 2.0 cm. Among them, one (1.2%) patient had bilateral tumors. During a median follow-up of 84 months, 12 of the 85 patients experienced structural recurrence. 13 patients had occult lymph node metastasis, and structural recurrence occurred in 2 patients. Factors that significantly affected disease-free survival were clinical N stage (cN0 vs. cN1, log-rank P < 0.001), pathological N stage (pN0 vs. pN1, P < 0.001), and preoperative calcitonin levels (≤ 250 vs. > 250 pg/mL, P = 0.017). After categorizing patients into four groups, patients with preoperative calcitonin levels > 250 pg/mL and cN1 or pN1 had a significantly worse prognosis. Patients with a primary tumor size of 2 cm or less, cN0, and preoperative calcitonin of 250 pg/mL or less can be classified as low-risk MTC patients. We used preoperative clinical information to identify low-risk MTC patients. Lobectomy with prophylactic CND may be a potential therapeutic approach., (© 2023. Springer Nature Limited.)

Background: A stepwise surgical approach with hemithyroidectomy and completion thyroidectomy was used to achieve definite characterization of follicular thyroid carcinoma (FTC). Choosing appropriate candidates for completion thyroidectomy has been controversial., Objective: The aim of this study was to clarify the selection criteria for completion thyroidectomy using telomerase reverse transcriptase (TERT) promoter mutation., Methods: A total of 87 FTC patients who had information about TERT promoter mutation from August 1995 to November 2020 were investigated. The cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each of the World Health Organization (WHO) 2017 classifications were calculated., Results: Of the 87 patients, 8 (9.2%) had initial distant metastasis and 15 (17.2%) had persistent disease or developed structural recurrence. The threshold diameter for initial distant metastasis, disease recurrence, and cancer-specific death was 2 cm in minimally invasive FTC (MI-FTC) with mutant TERT (M-TERT) and in encapsulated angioinvasive FTC (EA-FTC) with M-TERT, while that in MI-FTC with wild-type TERT (WT-TERT) and EA-FTC with WT-TERT was 4 cm. The cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each WHO 2017 classification was significantly different only in patients with WT-TERT (p = 0.001, p = 0.019, and p = 0.005, respectively)., Conclusions: The data suggest 2 cm as a critical threshold diameter for performance of completion thyroidectomy in MI-FTC with M-TERT and EA-FTC with M-TERT. TERT promoter mutational status can help select candidates for completion thyroidectomy., (© 2023. Society of Surgical Oncology.)

Background: No specific guideline exists for risk stratification based on lymph node (LN) status in pediatric thyroid cancer. The purpose of our study is to identify optimal values of lymph node ratio (LNR) and largest metastatic LN size for predicting recurrent/persistent disease, especially in children with lateral neck metastasis (N1b)., Methods: We conducted a retrospective study from January 1997 to June 2018 at Samsung Medical Center. A total of 50 papillary thyroid carcinoma (PTC) patients who underwent total thyroidectomy + both central neck dissection (CND) + modified radical neck dissection (MRND) (unilateral or bilateral) was enrolled., Results: The median follow-up duration was 60.8 months (range, 6.2-247 months). The mean age was 14.6 years, and the mean tumor size was 2.9 cm. Mean size of the largest metastatic LN was 1.5 cm. Mean value of central LNR was 0.6, and mean value of lateral LNR was 0.3. Largest metastatic LN size [HR = 2.0 (95% CI 1.0-4.0), p = 0.040] and lateral LNR [HR = 43.6 (95% CI 2.2-871.0), p = 0.014] were significant prognostic factors for recurrence. The optimal combination of lateral LNR and largest metastatic LN size to predict recurrence were 0.3 and 2.5 cm, respectively, with the largest AUC (AUC at 60 months = 77.4) and significant p-value (p = 0.009 and p = 0.021) (Table 3). Kaplan-Meier curves showed significant differences in recurrence-free survival (RFS) rates among four groups (Fig. 2A,2B)., Conclusions: In pediatric PTC patients with N1b, lateral LNR and largest metastatic LN size are significant predictors for recurrence. Children with lateral LNR > 0.3 or any metastatic lymph node > 2.5 cm in the largest dimension have higher risk for recurrence. Children are classified as extensive N1b if lateral LNR > 0.3 or pathologic N1 with largest LN size > 2.5 cm, and vice versa., Competing Interests: Declaration of Competing Interest No competing financial interests exist., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Although anaplastic thyroid carcinoma (ATC) is a fatal form of thyroid cancer with an overall survival of only a few months, there are some factors associated with longer survival. However, it remains unknown whether asymptomatic ATC differs from symptomatic ATC in terms of characteristics and overall prognosis. Therefore, we aimed to examine the clinicopathological characteristics and prognosis of asymptomatic ATC compared with those of symptomatic ATC. We retrospectively reviewed the medical records of 113 patients with ATC who were registered at our institution between November 1994 and July 2020. A total of 86 patients (59 women and 27 men; mean age, 66.9 ± 11.1 years) were enrolled for analysis. The clinicopathological characteristics of the ATC cohort were evaluated, and prognostic factors associated with disease-specific mortality were assessed. Of the 86 patients with ATC, 78 were symptomatic and eight were asymptomatic. Compared with the symptomatic group, the asymptomatic group had a younger age at diagnosis (59.3 ± 10.3 vs. 67.7 ± 11.0 years, p = 0.045), smaller tumor size (2.8 ± 1.2 vs. 5.8 ± 2.0 cm, p < 0.001), and longer survival period (37.5 ± 46.4, 9.5 ± 16.8 months, p < 0.001). However, the ATC component (%) of the tumor, sex, ultrasonographic risk category, and distant metastasis at diagnosis did not differ significantly between the two groups. In the multivariate Cox regression analysis, asymptomatic ATC (HR: 0.33, 95% CI 0.11-0.99, p = 0.045) and absence of distant metastasis (hazard ratio (HR): 0.56, 95% Confidence interval (CI) 0.35-0.88, p = 0.012) were associated with longer survival. Patients with asymptomatic ATC have a smaller tumor size, a longer survival period, and a younger age than those with symptomatic ATC. Being asymptomatic and having no distant metastasis were associated with longer survival in patients with ATC in a clinical setting., (© 2023. The Author(s).)

Background: Atrial fibrillation (AF) is occasionally diagnosed in individuals with Graves' disease. Definite treatments, including radioactive iodine therapy (RAIT) or surgery might lower the risk of AF in the literature. However, no studies have compared the effects of anti-thyroid drugs (ATDs), RAIT, and surgery on the risk of AF., Methods: This retrospective cohort study included 94,060 newly diagnosed Graves' disease patients and 470,300 controls from the Korean National Health Insurance database. The incidence of AF was evaluated in patients and controls. Patients were categorized based on treatment method into ATD (95.6%), RAIT (3.5%), and surgery (0.9%) groups. In the ATD group, the dose and duration of ATDs were calculated for each patient. In the RAIT and surgery groups, remission was defined as levothyroxine prescription., Results: Graves' disease patients had a 2.2-fold higher risk of developing AF than controls. Regardless of demographic factors, the patient group had a consistently higher risk of AF than controls, with the highest risk of AF (HR, 5.49) in the younger patient group. The surgery group had a similar risk of AF compared with controls, whereas the ATD (HR, 2.23) and RAIT (HR, 2.00) groups had increased risks of AF, even in patients reaching hypothyroid status after RAIT. Patients with higher dose or longer treatment duration of ATDs were at greater risk of AF., Conclusion: We observed differing risks of AF according to methods of treatment for Graves' disease, and that definite treatment can be an option for subjects needing sustained medical treatment considering the risk of AF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cho, Kim, Choi, Kim, Shin, Kim, Park, Kim, Chung, Han and Kim.)

The impact of serum thyroid hormone levels on thyroid cancer risk is unclear. Some studies reported that elevated thyroid-stimulating hormone (TSH) is associated with higher risk for incidence of thyroid cancer, but other studies reported no relationship. We conducted a large cohort study in 164,596 South Korean men and women who were free of thyroid cancer at baseline and underwent health examination with hormone levels of thyroid function. A parametric proportional hazard model was used to evaluate the adjusted hazard ratio (HR) and 95% CI. During 2,277,749.78 person-years of follow-up, 1280 incident thyroid cancers were identified (men = 593, women = 687). Among men, the multivariable-adjusted HR (95% CI) for thyroid cancer comparing low levels of TSH with normal levels of TSH was 2.95 (1.67-5.23), whereas the corresponding HR (95% CI) in women was 1.5 (0.88-2.55). High levels of free T4 and free T3 were also associated with incident thyroid cancer in both men and women. In clinical implication, overt hyperthyroidism is associated with thyroid cancer in both men and women. Within the euthyroid range, the highest tertile of TSH was associated with a lower risk of thyroid cancer than the lowest TSH tertile and the highest FT4 tertile was associated with a higher risk of thyroid cancer than the lowest FT4 tertile in both men and women. Our finding indicates that low levels of TSH and high levels of FT4, even within the normal range, were associated with an increased risk of incident thyroid cancer.

Backgruound: Telomerase reverse transcriptase (TERT) promoter mutations are associated with increased recurrence and mortality in patients with thyroid carcinoma. Previous studies on TERT promoter mutations were retrospectively conducted on a limited number of patients., Methods: We prospectively collected data on all consecutive patients who underwent thyroid carcinoma surgery between January 2019 and December 2020 at the Samsung Medical Center, Seoul, Korea. We included 2,092 patients with thyroid carcinoma., Results: Of 2,092 patients, 72 patients (3.4%) had TERT promoter mutations. However, the frequency of TERT promoter mutations was 0.5% in papillary thyroid microcarcinoma (PTMC) ≤1 cm and it was 5.8% in papillary thyroid carcinoma (PTC) >1 cm. The frequency of TERT promoter mutations was significantly associated with older age at diagnosis (odds ratio [OR], 1.12; P<0.001), larger primary tumor size (OR, 2.02; P<0.001), and aggressive histological type (OR, 7.78 in follicular thyroid carcinoma; OR, 10.33 in poorly differentiated thyroid carcinoma; OR, 45.92 in anaplastic thyroid carcinoma; P<0.001). Advanced T stage, advanced N stage, and distant metastasis at diagnosis were highly prevalent in mutated thyroid cancers. However, initial distant metastasis was not present in patients with TERT promoter mutations in PTMC. Although the C228T mutation was more highly detected than the C250T mutation (64 cases vs. 7 cases), there were no significant clinicopathological differences., Conclusion: This study is the first attempt to investigate the frequency of TERT promoter mutations in a real-world setting. The frequency of TERT promoter mutations in PTC was lower than expected, and in PTMC, young patients, and female patients, the frequency was very low.

Objective: Thyrotropin (TSH) suppression therapy is a standard treatment after surgery for differentiated thyroid carcinoma (DTC). It may be associated with osteoporosis in postmenopausal women. However, there are no guidelines for bone mineral density (BMD) testing intervals to screen for osteoporosis in these patients. Therefore, we evaluated the timing of repeated BMD testing in DTC patients with TSH suppression according to baseline T-scores., Design, Patients, and Measurement: We retrospectively evaluated 658 DTC patients who underwent BMD testing more than twice between January 2007 and January 2020. A 1:3 propensity score matching was conducted to compare the timing of repeated BMD tests between the DTC and non-DTC groups. We stratified the participants into four groups based on their baseline T-scores: normal (-1.00 or higher), mild osteopenia (-1.01 to -1.49), moderate osteopenia (-1.50 to -1.99), and severe osteopenia (-2.00 to -2.49). Additionally, the 10% of patients in each group that transitioned to osteoporosis were analysed., Results: The estimated BMD testing interval for 10% of patients who developed osteoporosis was 85 months for patients with initially mild osteopenia, 65 months for those with moderate osteopenia, and 15 months for those with severe osteopenia in the DTC group. In the non-DTC group, the testing intervals for mild, moderate, and severe osteopenia were 98, 57, and 13 months, respectively. On multivariate analysis, baseline T-score (mild osteopenia: hazard ratio [HR] 5.91, p = .105; moderate osteopenia: HR, 25.27, p = .02; and severe osteopenia: HR, 134.82, p < .001) and duration of TSH suppression (tertile 2: HR, 2.25, p = .005; Tertile 3: 1.78, p = .033) were independent risk factors for osteoporosis in the DTC group., Conclusion: This study provides guidance for the timing of repeated BMD tests in women over 50 years of age with TSH suppression. The rescreening interval for BMD testing can be modified based on the baseline T-score. The appropriate BMD testing intervals in female DTC patients were similar to those in non-DTC females., (© 2022 John Wiley & Sons Ltd.)

The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) provided a standardized framework for resulting thyroid fine-needle aspiration (FNA) specimens and introduced the low-risk category of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS). This indeterminate category has significantly evolved over time with the incorporation of molecular testing, reclassification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), and a shift toward more conservative management. Despite these refinements, AUS/FLUS remains a challenge, at both the diagnostic and therapeutic level. We review the criteria for AUS/FLUS and the associated controversies in rendering this diagnosis, while highlighting the importance of a multidisciplinary approach to managing atypical thyroid nodules., (© 2021 Wiley Periodicals LLC.)

Background: It is unclear if cigarette smoking and alcohol consumption are associated with thyroid cancer risk. Our aim was to explore for any associations between cigarette smoking and alcohol consumption with thyroid cancer, after adjusting for potential confounders. Methods: Using data from the Korean National Health Insurance database, we retrospectively identified individuals aged ≥20 years who participated in the 2009 health screening program and were followed until 2017. We estimated the adjusted hazard ratio (aHR) for the risk of thyroid cancer using a Cox proportional hazard model, adjusted for age, sex, regular exercise, monthly income, body mass index, diabetes mellitus, and dyslipidemia. Results: During a mean follow-up period of 8.33 ± 0.57 years, of 9,699,104 participants, 89,527 (0.9%) were diagnosed with thyroid cancer. Compared with those who never smoked, current smokers had a lower risk of thyroid cancer (aHR: 0.74, 95% confidence interval [CI]: 0.72-0.76), while ex-smokers did not (aHR: 0.98, 95% CI: 0.96-1.01). There was no significant dose-response relationship with regard to daily amount smoked, duration of smoking, or pack-years. A reduced risk of thyroid cancer was observed in subjects who reported the following categories of alcohol intake (compared with none): mild (aHR: 0.92, 95% CI: 0.90-0.93), moderate (aHR: 0.86, 95% CI: 0.84-0.89), and heavy (aHR: 0.86, 95% CI: 0.82-0.89). Inverse associations with thyroid cancer risk were observed regarding the number of drinking episodes per week and the number of drinks per occasion. A submultiplicative effect of smoking and alcohol consumption was observed ( p -interaction <0.001). Conclusions: We observed that thyroid cancer risk was inversely associated with smoking and alcohol consumption, with a significant interaction between these variables.

We previously reported that high thyroid-stimulating hormone (TSH) levels are associated with papillary thyroid microcarcinoma (PTMC) progression during active surveillance. However, validation with multicenter, long-term data, and identification of appropriate age or TSH levels are needed. This multicenter retrospective study enrolled PTMC patients under active surveillance with TSH measurements and ultrasonography. The primary outcome was PTMC progression (volume increase ≥50%, size increase ≥3 mm, or new lymph node (LN) metastasis). PTMC progression according to time-weighted average of TSH (TW-TSH) groups was compared using survival analyses in overall patients and each age subgroups (<40, 40-49, 50-59, and ≥60 years). The identification of TW-TSH cutoff point for PTMC progression and trend analysis of PTMC progression rate according to LT4 treatment were also performed. During 1061 person-years of follow-up, 93 of 234 patients (39.7%) showed PTMC progression (90, 17, and 5 patients for volume increase ≥50%, size increase ≥3 mm, and new LN metastasis, respectively). The highest TW-TSH group was the risk factor most strongly associated with PTMC progression (hazard ratio 2.13 (1.24-3.65); P = 0.006), but the impact was significant only in patients aged <40 or 40-49 years (hazard ratio 30.79 (2.90-326.49; P = 0.004), 2.55 (1.00-6.47; P = 0.049)). For patients aged <50 years, TW-TSH cutoff for PTMC progression was 1.74 mU/L, and PTMC progression rates successively increased in the order of effective, no, and ineffective LT4 treatment group (P for trend = 0.034). In young PTMC patients (<50 years), sustained low-normal TSH levels during active surveillance might be helpful to prevent progression.

Purpose: Follicular variant papillary thyroid carcinoma (FVPTC) is a problematic entity. FVPTCs are often misdiagnosed by the standard fine needle aspiration (FNA); in addition, FVPTCs represent a mixed group of tumors with two biologically distinct subtypes: The indolent encapsulated FVPTC and the aggressive infiltrative FVPTC. Recent changes in guidelines suggests that FVPTC management may be improved if subtypes can be determined preoperatively. Preoperative assays, FNA, core needle biopsy (CNB), and ultrasonography (US) were compared for their ability to identify and subtype FVPTCs to determine the most appropriate test to manage FVPTCs., Methods: The preoperative assays and clinicopathologic variables of 255 resected FVPTCs cases at Samsung Medical Center between 2012 and 2016 were retrospectively evaluated., Results: CNB had the overall best ability to manage FVPTCs with the highest rate of diagnosis indicating surgery, lowest rate of inconclusive results, high sensitivity (88.9%), specificity (87.7%), negative predictive value (97.0%), diagnostic odds ratio (DOR; 56.9), and excellent predictive ability (AUC 0.906) for differentiating FVPTC subtypes. US had a moderate DOR (12.8), good predictive ability (AUC 0.802), high sensitivity (75.0%) and specificity (81.0%). CNB and US both had significantly higher accuracy for discriminating FVPTC subtypes than FNA (AUC 0.908 and 0.877 > 0.671; p < 0.05). The excellent performance of CNB could be attributed to distinct histologic differences between FVPTC subtypes., Conclusion: CNB and US had superior performance to FNA in the identification and subtyping of FVPTC. In institutions with skilled and experienced operators, CNB is the preferred method for evaluating possible FVPTC lesions., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Follicular thyroid carcinoma (FTC) has different clinicopathological characteristics than papillary thyroid carcinoma. However, there are no independent systems to predict cancer-specific survival (CSS) in FTC. Telomerase reverse transcriptase (TERT) promoter mutations are associated with tumor aggressiveness. Thus, it could be a potential prognostic marker. The aim of this study was to refine the CSS risk prediction using TERT promoter mutations in combination with the fourth edition of World Health Organization (WHO 2017) morphological classification. We investigated 77 FTC patients between August 1995 and November 2020. Cox regression was used to calculate hazard ratios to derive alternative groups. Disease-free survival (DFS) and CSS predictability were compared using Proportion of variation explained (PVE) and C-index. CSS was significantly different in encapsulated angioinvasive (EA)-FTC patients stratified by TERT promoter mutations [wild-type (WT-TERT) vs. mutant (M-TERT); P < 0.001] but not in minimally invasive (MI)-FTC and widely invasive (WI)-FTC patients (P = 0.691 and 0.176, respectively). We defined alternative groups as follows: Group 1 (MI-FTC with WT-TERT and M-TERT; EA-FTC with WT-TERT), Group 2 (WI-FTC with WT-TERT), and Group 3 (EA-FTC with M-TERT; WI-FTC with M-TERT). Both PVE (22.44 vs. 9.63, respectively) and C-index (0.831 vs. 0.731, respectively) for CSS were higher in the alternative groups than in the WHO 2017 groups. Likewise, both PVE (27.1 vs. 14.9, respectively) and C-index (0.846 vs. 0.794, respectively) for DFS were also higher in the alternative groups than in the WHO 2017 groups. Alternative group harmonizing of the WHO 2017 classification and TERT promoter mutations is effective in predicting CSS in FTC patients, thereby improving DFS predictability., (© 2021. The Author(s).)

Background: Surgery is the most important curative treatment for medullary thyroid carcinoma (MTC). The relationship between surgeon volume (the number of surgeries performed) and short-term surgical outcomes, such as increased postoperative complication or costs, is well established. This study evaluated whether surgeon volume influenced long-term oncologic outcomes., Methods: We retrospectively reviewed 246 patients diagnosed with MTC after initial thyroid surgery from 1995 to 2019. After exclusion, 194 patients were eligible for inclusion in the study. Surgeons were categorized as low/intermediate volume (fewer than 100 operations per year) or high volume (at least 100 operations per year)., Results: Of the 194 included patients, 60 (30.9%) developed disease recurrence, and 9 (4.6%) died of MTC during the median follow-up of 92.5 months. Having a low/intermediate-volume surgeon was associated with high disease recurrence (log-rank test, p < 0.001). After adjustment for age, sex, tumor type (sporadic versus hereditary), primary tumor size, presence of central lymph node metastasis (LNM), presence of lateral LNM, extrathyroidal extension, and positive resection margin, surgeon volume was a significant factor for disease recurrence (hazard ratio 2.28, p = 0.004); however, cancer-specific survival was not affected by surgeon volume (hazard ratio 4.16, p = 0.115)., Conclusions: Surgeon volume is associated with long-term oncologic outcome. MTC patients will be able to make the best decisions for their treatment based on the results of this study., (© 2021. Society of Surgical Oncology.)

Serum thyrotropin (TSH) level after thyroid surgery affects the prognosis of differentiated thyroid cancer (DTC). However, the effects of preoperative serum TSH levels on the prognosis of DTC remain contradictory. In this study, to better understand the relationship between preoperative TSH levels and the prognosis of DTC, we performed pattern analysis of prognostic factors of DTC according to preoperative serum TSH levels. We retrospectively reviewed the clinical records of patients who were diagnosed and treated for DTC at the Samsung Medical Center, between 1994 and 2016. We reviewed preoperative serum TSH levels and performed a pattern analysis with prognostic risk factors for DTC. For pattern analysis, TSH was divided into 10 groups of equal fractions (TSH decile). We found a linear association between preoperative TSH levels and extra-thyroidal extension and lymph node metastasis. However, primary tumor size and initial distant metastasis showed a bimodal peak, which was similar to the pattern of overall and disease-specific death. We found that preoperative TSH range which showed the lowest mortality rate was about 0.8 to 1.59 mIU/L, which are slightly lower normal TSH levels. Although there was no linear trend, the primary tumor size, initial distant metastasis, and mortality of DTC were closely related with preoperative TSH decile and they showed a bimodal pattern. The results obtained in this study provide additional information for understanding the association between preoperative TSH levels and DTC prognosis., (© 2021. The Author(s).)

Background: Serum calcitonin level is a useful biomarker for predicting primary tumor size, the extent of lymph node, and distant metastasis in patients with medullary thyroid carcinoma (MTC). However, the association between preoperative serum calcitonin levels and long-term oncologic outcomes has not yet been established. The aims of this study were to determine the preoperative serum calcitonin cut-off value for predicting disease recurrence and to evaluate its prognostic value., Methods: Patients with MTC ( n = 169) who were treated at a tertiary referral hospital in Korea between 1995 and 2019 were enrolled. To determine the preoperative serum calcitonin cut-off value for predicting structural recurrence, the maximum of the standardized log-rank statistics of all possible cut-off values was used. Multivariable Cox regression analysis was used to determine prognostic factors for disease-free survival., Results: The overall disease-free survival rate was 75.7%. The preoperative serum calcitonin cut-off value that predicted structural recurrence was 309 pg/mL. Preoperative serum calcitonin levels of > 309 pg/mL were the strongest independent predictor of disease recurrence (hazard ratio (HR) 5.33, 95% confidence interval (85% CI) 1.67-16.96; P = 0.005). Lateral lymph node metastasis (HR 3.70, 95% CI 1.61-8.51; P = 0.002) and positive resection margins (HR 3.57, 95% CI 1.44-8.88; P = 0.006) were also significant predictors of disease recurrence., Conclusions: The preoperative serum calcitonin cut-off value is useful in clinical practice. It is also the best predictive factor for disease-free survival. Preoperative serum calcitonin levels may help determine the optimal postoperative follow-up strategy for patients with MTC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Park, Park, Park, Choe, Chung, Woo, Choi, Kim, Chung and Kim.)

Background: Some papillary thyroid microcarcinomas (PTMCs) may progress with tumor enlargement or development of new lymph node (LN) metastasis during active surveillance (AS). This study evaluated the relevant predictors of disease progression, especially new cervical LN metastasis. Methods: This was a long-term follow-up study conducted using a previous multicenter cohort of AS in Korea. After excluding 54 (14.2%) patients with a short follow-up duration, 326 PTMC patients were evaluated for tumor kinetics, including changes in tumor volume (TV) and TV doubling time (TVDT). Results: During a median follow-up duration of 4.9 years, 17 (5.2%, 95% confidence intervals [CI] 2.7-7.6%) patients showed a maximal diameter increase of ≥3 mm after a median of 4.0 years follow-up, while 9 (2.8%, CI 1.0-4.5%) developed new LN metastasis after a median of 2.2 years follow-up. New cervical LN metastasis occurred exclusively of a maximal diameter increase of ≥3 mm. The prevalence of new development of LN metastasis was higher in patients with TVDT <5 years (7.4%) than in those with TV ≥50% (3.2%). Furthermore, only TVDT <5 years was significantly associated with LN metastasis ( p  = 0.002). In univariate and multivariate analyses, TVDT <5 years was an independent risk factor for disease progression with respect to new development of LN metastasis (hazard ratio [HR] = 6.51, CI 1.73-24.50; p  = 0.002) and tumor enlargement (HR = 20.89, CI 5.78-75.48; p  < 0.001). Finally, 86 (22.6%) patients underwent delayed surgery, and the most common reason was patient anxiety. Conclusions: TVDT <5 years is a predictor of disease progression during AS in terms of new LN metastasis development as well as tumor enlargement. Determination of TVDT in the early phase of AS could help in predicting disease progression, tailoring follow-up intensity of AS and in determining if early surgical intervention is needed.

Background: Although the incidence of thyroid cancer had been increasing until a few years ago, a decrease has been observed in the last years, probably due to the reduction of the screening tests in Korea. Childhood thyroid cancer has been increasing in the past with the same trend as in adults, but there have been few reports on recent trends. We analyzed the trends of thyroid cancer in Korean children and related factors., Methods: From national statistics and cancer register database, the data of age-specific incidence rate in Korean childhood thyroid cancer from 1999 to 2017 was obtained, and levels of seaweed intake, the number of computed tomography (CT) and neck ultrasonography (US), obesity prevalence rate, and smoking and alcohol consumption rates in children were analyzed., Results: The age-specific incidence of thyroid cancer in Korean children has increased in both genders between 1999 and 2017 (2.0 in 1999 vs. 7.2 in 2017, per population of 100,000), especially in the age group of 14-18 years (1.5 in 1999 vs. 5.5 in 2017, per population of 100,000). During the same period, levels of seaweed intake, number of CT scans and neck US, and prevalence of obesity in children increased significantly, while childhood smoking and alcohol consumption rates decreased., Conclusion: Unlike the adult thyroid cancer in Korea, childhood thyroid cancer continues to increase, and the cause might be accompanied by actual increases due to the environmental factors such as excessive iodine intake, exposure to medical radiation, and increased obesity prevalence as well as the screening effect., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Park, Park, Kim, Kim, Jang and Chung.)

Background: Anaplastic thyroid cancer (ATC) has dismal prognosis and there is no effective treatment. We aimed to evaluate the efficacy of tyrosine kinase inhibitor (TKI) therapy in real-world clinic and to suggest the most effective treatment modality according to the combination of treatments., Methods: This retrospective study evaluated clinical outcomes and cause of death with multimodal treatments in patients with ATC at Samsung Medical Center., Results: A total of 120 patients received anti-cancer treatment for ATC. Seventy-seven (64.2%) patients underwent surgery, 64 (53.3%) received radiotherapy, 29 (24.2%) received cytotoxic chemotherapy, and 19 (15.8%) received TKI therapy. In the TKI therapy group, eight achieved partial response (three with lenvatinib and five with dabrafenib plus trametinib), and two patients with lenvatinib showed stable disease. Median progression-free survival (PFS) of the TKI therapy group was 2.7 months (range: 0.1-12.7) and their median overall survival (OS) was 12.4 months (range: 1.7-47.7). Patients who received surgery or radiotherapy for local control showed superior OS than those who did not. In a multivariate analysis, surgery, TKI therapy, younger age, and no distant metastasis were associated with favorable OS. The combination of surgery, radiotherapy, and TKI therapy (median OS: 34.3 months, 6-month survival rates: 77.8%) was the most effective. Compared to the era without TKI therapy, distant metastasis has recently become the major cause of death in ATC over airway problems., Conclusions: Multimodality treatment including TKI therapy demonstrated prolonged survival with dabrafenib plus trametinib as the most effective therapeutic option demonstrated for BRAF mutant ATC patients.

Objective: We evaluated the preoperative diagnostic values of ultrasound (US), fine-needle aspiration (FNA) and core needle biopsy (CNB) leading to surgery in patients with FTC., Methods: From October 1994 to July 2016, 298 patients with FTC who had preoperative US images and underwent US-guided FNA or CNB and surgery were included in this study. We evaluated the results of preoperative FNA or CNB based on the Bethesda system and the US findings according to the Korean thyroid imaging reporting and data system (K-TIRADS)., Results: Predominant US features of FTC showed solid, hypo- or iso-echogenicity, oval smooth margin and halo with no calcification. Based on K-TIRADS, 140 (47.0%) patients with FTC were categorized as low suspicion, 133 (44.63%) as intermediate suspicion and 25 (8.4%) as high suspicion at US. Considering only FNA cytology (n = 230), 6.9% were revealed as Bethesda class I, 16.1% as class II, 37.0% as class III, 29.1% as class IV and 10.9% as class V. Considering the 68 cases with CNB results, 2.9% were revealed as class I, 4.4% as class II, 20.6% as class III and 72.1% as class IV. Despite multiple FNAs, 16.7% of the 84 patients with FTC still obtained Bethesda class I or class II. CNB results in patients with FTC had a significantly higher rate of Bethesda class IV compared to the FNA results (P < .001). FTCs with distant metastasis exhibited a significantly higher rate of Bethesda classes IV and V compared to those without distant metastasis (P = .004)., Conclusion: Surgery for FTC is deferred only with preoperative US and FNA. CNB in patients with FTC can lead to surgery better than FNA. Therefore, if the US feature is characteristic and a serially growing large nodule is suspected, the first attempt of CNB may be helpful in selecting a surgical candidate., (© 2020 John Wiley & Sons Ltd.)

The incidence of thyroid cancer (TC) has been increasing in many countries and concerns about overdiagnosis are also widely shared. However, early detection may be helpful in some high-risk TC patients, such as those with initial distant metastasis. We conducted this study to evaluate the usefulness of early detection in TC patients with initial distant metastasis. We retrospectively reviewed the clinical data of 13,249 TC patients, and found 127 patients with initial distant metastasis. Enrolled patients were divided into two groups according to the diagnostic periods; before and after 2004, when the early detection of TC by ultrasonography began in earnest in Korea. Patients were also divided into two groups according to the presence of symptoms. Prior to 2004, 33 patients (1.7% of TC patients) were diagnosed with TC with initial distant metastasis and 16 (48.5%) of them died. After 2004, 94 patients (0.8% of TC patients) were diagnosed with TC with initial distant metastasis and 29 (30.9%) of them died. Prior to 2004, the disease-specific death rates were similar between the asymptomatic and symptomatic groups (46.2% vs. 50.0%, P = 0.566). Conversely, after 2004, the asymptomatic group showed a significantly lower disease-specific death rate as compared with that of the symptomatic groups (17.2% vs. 60.0%; P < 0.001). Early detection had a significant positive impact on survival outcomes only after 2004, especially in asymptomatic TC patients with initial distant metastasis.

Background: Treatment for patients with radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC) is challenging. Recently, two tyrosine kinase inhibitors (sorafenib and lenvatinib) have been approved and showed benefits for progression-free survival with tolerable adverse events. Methods: This is an extension study of a previous multicenter, retrospective cohort study of real-world experience in treating 98 patients with progressive RAI-refractory DTC with sorafenib. The primary endpoint was overall survival (OS). The efficacy of lenvatinib as salvage therapy after disease progression on first-line sorafenib was evaluated by comparing outcomes in 32 patients who were treated with lenvatinib with 41 patients who were not and therefore served as a no salvage treatment group. Results: The median OS of all 98 patients treated with sorafenib was 41.5 months, and the median progression-free survival was 13.5 months. Patients without disease-related symptoms before sorafenib treatment had better OS than those with symptoms (hazard ratio [HR] = 0.56 [95% confidence interval, CI 0.31-0.99], p  = 0.048). Larger tumor size was associated with a minimally increased risk of death (HR = 1.02 [CI 1.00-1.03], p  = 0.049). Best tumor response was not associated with OS ( p  = 0.490). Lenvatinib salvage treatment significantly improved OS in patients receiving it compared with those who did not (HR = 0.28 [CI 0.15-0.53], p  < 0.001). The median OS from the time of disease progression after first-line sorafenib treatment was 4.9 months in no salvage treatment group, whereas it was not reached in the lenvatinib salvage group. Conclusions: The absence of disease-related symptoms and smaller tumor burden was associated with survival benefits of first-line sorafenib treatment in patients with progressive RAI-refractory DTC. Lenvatinib salvage therapy was effective in improving OS in patients with disease progression after first-line sorafenib.

Background: Cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is a rare subtype of PTC, which occurrs predominantly in young women. This disease much more frequently presents in patients with familial adenomatous polyposis (FAP). FAP is an autosomal dominant inherited disease, which arises from germline mutations in the adenomatous polyposis coli ( APC ) gene. To clarify the distinctive clinical features of CMV-PTC, a comparison study was performed between familial types and sporadic types. Methods: Between 2007 and 2018, 15 CMV-PTC patients underwent thyroidectomy in Samsung Medical Center. The clinical features of these patients were retrospectively reviewed. Results: All patients were women with a median age of 26 years (range 17-46 years). The median maximum diameter was 1.0 cm (range 0.4-3.5 cm). All tumors underwent immunostaining and showed nuclear and/or cytoplasmic staining for β-catenin. On ultrasonography, most nodules had benign-looking features (well-defined, hypoechoic, and oval to round shapes without calcification), but a few nodules had capsular invasion and taller than wide shape. On preoperative fine-needle aspiration cytology, five patients (33%) were diagnosed as CMV-PTC, nine (60%) as PTC, but one (7%) as follicular neoplasm or PTC-follicular variant. Six patients (40%) had FAP, and four of them had total colectomy due to FAP. Five of them had a family history of FAP or colon cancer, or thyroid cancer. Germline mutations in the APC gene were found in all six patients with CMV-PTC associated with FAP, and five of them had de novo mutations. All patients with FAP-associated CMV-PTC had multiple tumors. All CMV-PTC patients had excellent response to initial therapy. Conclusions: Because of the association between FAP or colon cancer with multifocal CMV-PTC, we confirm that mutational analysis of the APC gene and colonoscopy should be carried out in these patients when multiple thyroid tumors are found.

Background: The current American Thyroid Association risk-stratification system for papillary thyroid carcinoma (PTC) incorporates the number and size of positive lymph nodes (LNs) but places less weight on extranodal extension (ENE). This study investigated how to incorporate ENE into the current system to predict recurrence better in PTC N1 patients. Methods: A total of 369 N1 PTC patients without distant metastasis were enrolled. The combination of number of positive LNs and LNs with ENE that had the highest C-index were identified with multivariable Cox proportional hazards models. ENE number was incorporated into the current system considering the recurrence rate and unadjusted and adjusted hazard ratios (HRs) of the subgroups. Kaplan-Meier curves for recurrence based on current and alternative systems were compared by log-rank test. Results: The recurrence rate for the subgroup with five or fewer positive LNs and one to three ENEs (7/61; 11.5%) was higher than that of the subgroup with five or fewer positive LNs without ENE (5/129; 3.9%; adjusted HR = 3.42 [confidence interval (CI) 0.99-11.75]; p  = 0.050). In contrast, adjusted HRs of the subgroup with more than five positive LNs and one to three ENEs (2.33 [CI 0.52-10.35]) or with four or more ENEs (3.86 [CI 1.05-14.17]) were not higher than those of the subgroup with more than five LNs without ENE (4.47 [1.16-17.19]). Incorporating ENE into the current system as an intermediate-risk group yielded a lower log-rank p -value (0.05 vs. 0.01) than the current system. Conclusions: The presence of ENE in low volume LN metastasis confers an intermediate risk of recurrence. Incorporating ENE into the current system allows more accurate decisions regarding further management of PTC N1 patients.

Purpose: Long-term effects of iatrogenic hypothyroidism on renal function from thyroid hormone withdrawal during radioactive iodine therapy (RAIT) have not been studied, especially in subjects with mildly impaired renal function. We compared renal function in thyroid cancer subjects according to preparation method of either thyroid hormone withdrawal (THW) or injection of recombinant human thyrotropin (rhTSH)., Methods: This retrospective study enrolled 241 thyroidectomized patients (rhTSH group, n = 87 and THW group, n = 154). Changes in glomerular filtration rate (GFR) were measured prior to surgery, at the time of RAIT, and during a regular follow-up at least one year after RAIT., Results: Baseline renal function was comparable between the rhTSH group and the THW group (91.4 mL/min/1.73 m 2 vs. 92.4 mL/min/1.73 m 2 ). At the time of RAIT, GFR was significantly decreased in the THW group (70.6 mL/min/1.73 m 2 , -23.6%), whereas renal function was preserved in the rhTSH group (85.4 mL/min/1.73 m 2 , -6.6%). In the THW group, renal function was fully recovered within 6 months after RAIT and was maintained up to 24 months, even in subjects with baseline GFR less than 90 mL/min/1.73 m 2 ., Conclusions: THW for RAIT preparation induced considerable reduction in renal function, but this change was transient. In contrast, injection of rhTSH did not decrease renal function, making it a good option for RAIT preparation for subjects with renal dysfunction.

Background: Patients with differentiated thyroid carcinoma (DTC) are staged according to the single age cut point in addition to anatomic extent. A novel staging system is needed to properly show the character and prognosis of DTC by considering age as a continuous variable. We aimed to refine stage and prognostic groups of the eighth edition tumor-node-metastasis (TNM-8) staging system for DTC and to suggest a possible revision., Methods: We conducted a retrospective data abstraction study of patients with newly diagnosed DTC who were treated at one of two tertiary referral centres in Seoul, Korea between 1994 and 2005. We used recursive partitioning analysis to derive a new staging classification (TNM-RPA) and compared its prediction of cancer-specific survival with that of TNM-8., Results: The cohort comprised 6342 patients with DTC who were followed up for a median of 11.4 years. Higher TNM-RPA groups were associated with increased risk of death (10-year cancer-specific survival for stages IA, IB, IIA, IIB, III, and IV: 99.6%, 98.1%, 93.0%, 92.4%, 75.1%, and 56.6%, respectively; P < 0.001). The C-index values were 0.869 (95% CI, 0.833-0.905) for the TNM-RPA and 0.819 (0.789-0.850) for TNM-8. The proportions of variance explained for the ability of the TNM-RPA and TNM-8 stages to predict cancer-specific survival were 7.1% and 5.7%, respectively., Conclusion: This study presents a RPA-based TNM stage groupings that incorporate multiple age cutoffs and essential anatomic information, which can be conveniently used to facilitate the individual prediction of long-term cancer-specific survival in patients with DTC., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Recent guidelines advocate unilateral thyroidectomy for low-risk 1-cm to 4-cm differentiated thyroid cancer (DTC). This study was designed to examine the association between the extent of thyroidectomy and oncologic outcomes in patients with 1-cm to 4-cm DTC., Materials and Methods: From April 1978 to December 2011, 16 057 patients with DTC underwent thyroidectomy at Yonsei University Hospital. Among them, 5266 (32.8%) patients were classified as having 1-cm to 4-cm DTC and were enrolled in this study. Clinicopathologic features and prognostic results (disease-free survival [DFS] and disease-specific survival [DSS] rates) were analyzed by retrospective medical record review. The mean follow-up duration was 57.3 ± 58.1 months., Results: Of tumor subtypes in the study group, papillary thyroid carcinoma was the most common (97.5%) and follicular thyroid carcinoma occurred at a rate of 2.5%. In this study, the mean tumor size was 1.84 ± 0.74 cm. Patients had extrathyroidal extension (69.3%), multiplicity (35.1%), bilaterality (26.4%), central lymph node metastasis (53.0%), and lateral neck node metastases (19.9%). Of the 5266 patients, 4292 (81.5%) underwent total thyroidectomy and 974 (18.5%) had lobectomies. Recurrence rates in the total thyroidectomy and lobectomy groups were 5.7% and 9.4%, respectively. The lobectomy group had lower DFS (P = .007) and higher DSS (P = .034) than the total thyroidectomy group. A multivariate analysis for DFS revealed that tumor size, N classification, and extent of thyroidectomy were independent risk factors. On multivariate analysis, independent risk factors for DSS were age, sex, tumor size, and M classifications., Conclusion: Although extent of thyroidectomy does not affect DSS, total thyroidectomy is beneficial for reducing recurrence in patients with 1-cm to 4-cm DTC. However, if such tumors have such low-risk features as being unifocal, intrathyroidal, and lymph node metastasis-negative, extent of thyroidectomy does not affect oncologic outcome and lobectomy may be sufficient., (© 2018 Wiley Periodicals, Inc.)

Context: Despite advances in thyroid cancer staging systems, considerable controversy about the current staging system for medullary thyroid carcinoma (MTC) continues., Objective: We aimed to evaluate the prognostic performance of the current eighth edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control TNM staging system (TNM-8) and the alternative proposed prognostic stage groups based on recursive partitioning analysis (TNM-RPA)., Design, Setting, and Patients: We retrospectively analyzed 182 patients with MTC treated at a single tertiary Korean hospital between 1995 and 2015., Interventions and Main Outcome Measures: Survival analysis was conducted according to TNM-8 and TNM-RPA. The area under the receiver-operating characteristic curve (AUC), the proportion of variation explained (PVE), and the Harrell concordance index (C-index) were used to evaluate predictive performance., Results: Under TNM-8, only two (1.1%) patients were downstaged compared with the seventh edition of the AJCC TNM staging system (TNM-7). The AUC at 10 years, PVE, and C-index were 0.679, 8.7%, and 0.744 for TNM-7 and 0.681, 8.9%, and 0.747 for TNM-8, respectively. Under TNM-RPA, 104 (57.14%) patients were downstaged compared with TNM-8. TNM-RPA had better prognostic performance with respect to cancer-specific survival (AUC at 10 years, 0.750; PVE, 20.9%; C-index, 0.881)., Conclusions: The predictive performance of the revised TNM-8 in patients with MTC has not changed despite its modification from TNM-7. The proposed changes in TNM-RPA were statistically valid and may present a more reproducible system that better estimates cancer-specific survival of individual patients.

Background: Active surveillance has been introduced as a management option for low-risk papillary thyroid microcarcinoma (PTMC) due to its mostly indolent course., Methods: This was a multicenter study of 370 PTMC patients who underwent active surveillance more than one year. The changes in volume and maximum diameter between initial and last ultrasonography were evaluated to identify the natural course of PTMC during active surveillance., Results: Patients' age at diagnosis was 51 ± 12 years, and 110 (30%) patients were <45 years of age. The initial maximum diameter and volume of PTMCs were 5.9 ± 1.7 mm and 81.0 ± 77.7 mm 3 , respectively. During the median 32.5 months of follow-up, 86 (23.2%) patients were found to have an increase in tumor volume, and 13 (3.5%) patients showed an increase in the maximal diameter of the tumor. The cumulative incidence of volume increase gradually rose with time (6.9%, 17.3%, 28.2%, and 36.2% after two, three, four, and five years, respectively). The risk of volume increase in patients <45 years of age was twice as high as in older patients (p = 0.002). There was no significant difference in tumor size change according to sex, levothyroxine treatment, or presence of Hashimoto's thyroiditis. During the period, 58 (15.7%) patients underwent delayed thyroid surgery due to anxiety (37.9%), tumor size increase (32.8%), or appearance of cervical lymph node metastasis (8.6%). Lymph node metastasis was found in 29.3% of patients on pathological examination., Conclusions: A significant number of PTMCs grow during active surveillance, and tumor volume change is a more sensitive means of evaluating tumor growth. Active surveillance can be carefully applied for selected patients. Although it is not contraindicated, it should be applied more cautiously for younger patients.

Objectives: This study aimed to evaluate the proposed changes in the eighth edition of the tumor-node-metastasis staging system (TNM-8) compared with the seventh edition (TNM-7) in terms of pathologic subtypes, using a large multicenter thyroid cancer cohort., Materials and Methods: We retrospectively reviewed 7717 patients with papillary (PTC) and 273 with follicular thyroid carcinoma (FTC) who underwent thyroid surgery between 1996 and 2005. We assessed the proportion of variation explained (PVE) to compare the predictive accuracy of disease-specific survival (DSS)., Results: During a median 11.3 years of follow-up, 169 (2%) disease-specific deaths were recorded. In patients with PTC, the 10-year DSS rates of stages I, II, III, and IV disease in TNM-8 were 99.6%, 95.7%, 81.5%, and 54.8%, respectively; the corresponding rates in TNM-7 were 99.6%, 98.4%, 98.4%, and 90.1%, respectively. In patients with FTC, the 10-year DSS rates of stages I, II, III, and IV disease in TNM-8 were 97.2%, 69.8%, 50.0%, and 45.5%, respectively; the corresponding rates in TNM-7 were 98.3%, 90.0%, 92.3%, and 42.1%, respectively. Comparing TNM-7 and TNM-8, the PVE values increased from 3.4% to 4.7% in the PTC group, whereas they decreased from 17.5% to 14.5% in the FTC group., Conclusion: Our study suggests that the changes in TNM-8 have improved the clinical usefulness of the TNM staging system in terms of predicting DSS in patients with PTC but not FTC. Further studies to establish a more predictable TNM staging system that focuses on patients with FTC are necessary., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: Based on the tumor-node-metastasis staging system, eighth edition (TNM-8), N1b is no longer used as a variable to determine final stage in papillary thyroid carcinoma (PTC). We aimed to evaluate the predictability of a simple modification of the TNM staging with N1b classification in a large multicenter thyroid cancer cohort., Materials and Methods: This study included 7717 patients with PTC who underwent thyroid surgery between 1996 and 2005 from six tertiary hospitals. We classified patients with stage II into stage IIA and IIB with modified-TNM: older patients with N1b disease were classified as stage IIB, while remaining patients were classified as stage IIA., Results: The mean age was 46.2 years, and 24% were aged ≥55 years. In older patients, the 10-year disease-specific survival (DSS) rate of N1b disease (86.3%) was approximately 10% lower than that of N1a disease, and patients with N1b had significantly poorer DSS than those with N1a (HR = 3.3, p < 0.001). When the modified-TNM was applied, DSS curves between stage groups significantly differed (p < 0.001), and the relative risk of DSS in stage IIB patients was 2.3 times higher than in stage IIA patients (p < 0.001). The proportion of variation explained value of the modified-TNM was 4.9% and that of the TNM-8 was 4.7%., Conclusion: This multicenter study reveals that the presence of lateral lymph node metastasis affects disease mortality in PTC, especially in older patients. The sub-classification of stage II in older patients improves DSS predictability. This simple modification of TNM-8 provides better prognostic information for patients with PTC., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

We modified the nondiagnostic/unsatisfactory category of the Bethesda system for reporting thyroid cytopathology to inform cytopathologic adequacy to better stratify the malignancy risk. Malignancy rates from 1,450 cytopathologic specimens not satisfying adequacy criteria from April 2011 to March 2016 were calculated based on sub-classification of the nondiagnostic/unsatisfactory category and sonographic patterns using matched surgical pathology. Rates were compared with those of 1,446 corresponding adequate specimens from July to December 2013. Upon resection, 63.2% of nondiagnostic, 36.7% of unsatisfactory + benign, 72.5% of unsatisfactory + atypia (follicular lesion) of undetermined significance, 98.1% of unsatisfactory + suspicious for malignancy, and 100.0% of unsatisfactory + malignant cases were confirmed to be malignant on surgical pathology. In nodules with inadequate specimens, those with high suspicion sonographic patterns had a malignancy rate (93.2%) higher than the others (45.5%) (p < 0.001). Nodules with unsatisfactory + benign specimens had a higher malignancy rate (36.7%) than satisfactory benign specimens (14.3%) (p = 0.020). For atypia (follicular lesion) of undetermined significance, the malignancy rate of inadequate specimens (72.5%) was higher than that of adequate specimens (51.3%) (p = 0.027). Sparse cellular samples with a few groups of benign follicular cells should not represent a benign lesion. There might be value in qualifying atypia (follicular lesion) of undetermined significance cases less than optimal.

Objectives: The efficacy of radioiodine remnant ablation (RRA) for patients with differentiated thyroid carcinoma (DTC) with gross extrathyroidal extension (ETE) is well described in observational studies. However, its role in gross ETE invading only strap muscles, T3b category in the newly proposed eighth edition of the TNM staging system, is currently unknown., Methods: This study retrospectively analyzed 260 DTC patients with ETE invading only strap muscles who underwent thyroidectomy at a tertiary Korean hospital between 1994 and 2005. Cancer-specific survival (CSS) and recurrence-free survival (RFS) in the no RRA (n = 13), low RRA activity (<3.7 GBq, n = 80), and high RRA activity (≥3.7 GBq, n = 167) groups were studied., Results: No significant differences were observed between low and high activity RRA groups in terms of 10-year CSS (97.3% versus 99.3%; HR 0.23, 95% CI 0.02-2.57; p = .235) and RFS (86.8% versus 88.8%; 0.90, 0.40-2.03; p = .804). In the no RRA group, no patients died of cancer, and only one developed structural recurrence. In Cox regression analyses with inverse probability of treatment weighting adjusted for clinicopathologic risk factors, high activity RRA was not related to recurrence outcomes compared to low activity (HR 0.60, 95% CI 0.26-1.35; p = .214)., Conclusions: Long term oncologic outcomes did not significantly differ between low versus high activity RRA groups, which suggests that low activity RRA might be sufficient in patients with DTC with gross ETE invading only strap muscles. Further studies are needed to clarify the optimal activity of RRA in these patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: In the eighth edition of the AJCC staging system for differentiated thyroid carcinoma (DTC), minimal extrathyroidal extension (ETE) is no longer a determinant of T3 category. Instead, gross ETE invading only strap muscles has been designated as a new T3b category. The long-term prognosis of patients with DTC and gross ETE invading only strap muscles was investigated., Methods: This was a retrospective analysis of patients who underwent thyroidectomy between 1996 and 2005. Differences in cancer-specific and recurrence-free survival according to extent of ETE were assessed., Results: A total of 3174 patients with DTC were included. No significant differences were observed in 10-year cancer-specific survival among patients with no ETE (98·6 per cent), microscopic ETE (98·3 per cent) and gross ETE invading only strap muscles (98·9 per cent) (P = 0·375). The 10-year recurrence-free survival rate for patients with gross ETE invading only strap muscles (89·2 per cent) was shorter than that for patients with no ETE (93·7 per cent; P = 0·016), but similar to that of patients with microscopic ETE (90·3 per cent). In univariable analysis, patients with gross ETE invading only strap muscles had a significantly higher risk of recurrence than those with no ETE (hazard ratio (HR) 1·67, 95 per cent c.i. 1·10 to 2·55; P = 0·017). In multivariable analysis, gross ETE invading only strap muscles was not an independent predictor of recurrence (HR 1·09, 0·71 to 1·69; P = 0·685)., Conclusion: Although gross ETE invading only strap muscles may provide prognostic information about long-term recurrence, it does not affect mortality. The actual impact of gross ETE invading only strap muscles will be important in revising the staging system in the future., (© 2018 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: Metformin, the most widely used drug for type 2 diabetes, has recently attracted attention with regard to its antitumor activity. However, clinical studies have yielded conflicting results regarding the association between metformin and thyroid cancer development, despite its antitumor effect in preclinical studies., Methods: This is a retrospective cohort study using the Korean National Health Insurance claim database. Matched populations of 128,453 metformin users and 128,453 non-users were analyzed for thyroid cancer incidence. Metformin users were categorized into lowest, middle, and highest tertiles according to cumulative dose or duration of metformin therapy., Results: Thyroid cancer developed in 340 (0.26%) metformin users and 487 (0.38%) non-users during a mean follow-up of 7.2 years (hazard ratio = 0.69 [confidence interval 0.60-0.79]; p < 0.001). The incidence of thyroid cancer per 10 5 person-years was 51.6 in metformin non-users. For metformin users, the incidence was 84.5 for <529,000 mg, 20.6 for 529,000-1,007,799 mg, and 6.3 for >1,007,799 mg; 86.3 for <1085 days, 20.3 for 1085-2094 days, and 4.7 for >2094 days for duration of therapy. The hazard ratio for thyroid cancer decreased significantly in metformin users as a function of dose and duration of metformin therapy., Conclusions: Metformin appears to be associated with a preventive effect on thyroid cancer development in a nationwide population-based study, but is not effective in the early phase of treatment. Considering the increasing prevalence of obesity and the role of insulin resistance in the development of cancer, metformin might be the preferred treatment for its dual anti-diabetic and antitumor effects.

Aims: The non-invasive encapsulated follicular variant of papillary thyroid carcinoma (FVPTC) has been managed as a low-risk malignancy. Recently, a proposal was made to reclassify this tumour type as a premalignant lesion and rename it non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This study aims to provide the first comprehensive study on molecular genotype-phenotype correlations of encapsulated FVPTC., Methods and Results: This study was performed on 177 consecutive FVPTCs from January 2014 to April 2016. These were classified as non-invasive encapsulated FVPTC (n = 74) invasive encapsulated FVPTC (n = 51), and infiltrative FVPTC (n = 52), according to standard criteria, by two independent pathologists. Genetic alterations and other clinicopathological information were compared. BRAF V600E was found in 12.2% (non-invasive) and 11.8% (invasive) of encapsulated FVPTCs, and in 34.6% of infiltrative FVPTCs (P = 0.001). Mutation in encapsulated FVPTCs was limited to cases with rare or abortive papillae. RET-PTC1 and RET-PTC3 rearrangements were present (11.5%) only in infiltrative FVPTCs. In contrast, NRAS, HRAS and KRAS mutations were observed more often in encapsulated FVPTCs (48.6% in non-invasive and 66.7% in invasive) than in infiltrative FVPTCs (15.4%) (P < 0.001). Preoperative cytological examination did not distinguish between non-invasive and invasive encapsulated FVPTCs, whereas infiltrative FVPTC was more likely to be Bethesda class V/VI than the encapsulated type (60.4% versus 38.1%; P = 0.01)., Conclusions: There were no differences in clinicopathological or molecular profiles between non-invasive and invasive encapsulated FVPTCs, except in vascular and capsular invasion. Therefore, the diagnosis of NIFTP, like that of follicular adenoma, may require surgical resection and exclusion of those tumours with any papillae., (© 2017 John Wiley & Sons Ltd.)

Background: In the eighth edition, TNM staging system omits location of nodal metastasis as a criterion for staging patients with papillary thyroid cancer (PTC). Accordingly, all of non-metastatic N1b PTC patients are classified as stage I or II solely according to an age-cutoff of 55 years. We hypothesized that incorporating other lymph node (LN) factors into TNM staging system would better predict cancer-specific mortality (CSM) in N1b patients., Methods: We enrolled 745 N1b PTC patients without distant metastasis. Alternative prognostic LN factors and cut-off points were assessed using Cox regression and time-dependent ROC analysis. Alternative prognostic groupings were derived based on minimal hazard differences for CSM among groups stratified by LN risk and age. We assessed accuracy of CSM prediction., Results: Lateral LN ratio (LNR) >0.3 and largest LN size >3 cm were prognostic factors for CSM. Stage II patients (eighth edition) with LN risk (lateral LNR >0.3 or largest LN size >3 cm) had a much higher CSM rate (20.9%) than those in the same stage without LN risk (3.2%). Alternative prognostic grouping (Group 1, <55 years without LN risk; Group 2, <55 years with LN risk or ≥55 years without LN risk; and Group 3, ≥55 with LN risk) achieved higher proportions of variance explained (PVEs) for predicting CSM (10.7%) than those of the eighth edition TNM staging system (4.8%)., Conclusions: The proposed grouping for N1b patients using LN risk can distinguish patients with poor prognosis from those with good prognosis better than the eighth edition TNM staging system., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Sorafenib, a multi-kinase inhibitor, is approved for the treatment of patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). This study evaluated the efficacy and safety of sorafenib in real-world clinical practice and compared the results to those of the DECISION trial. The clinical features associated with better clinical outcomes after sorafenib treatment were also evaluated., Methods: This multicenter, retrospective cohort study evaluated 98 patients with progressive RAI-refractory DTC who were treated with sorafenib in six tertiary hospitals in Korea. The primary objective was the progression-free survival (PFS) according to Response Evaluation Criteria In Solid Tumors v1.1. Overall survival, response rate (defined as the best objective response according to Response Evaluation Criteria In Solid Tumors v1.1), and safety were also evaluated., Results: The median PFS was 9.7 months; median overall survival was not reached during follow-up. Partial responses and stable disease were achieved in 25 (25%) and 64 (65%) patients, respectively. Stable disease of >6 months was achieved in 41 (42%) patients. Subgroup analyses identified several prognostic indicators of a better PFS: absence of disease-related symptoms (hazard ratio [HR] = 0.5; p = 0.041), lung-only metastasis (HR = 0.4; p = 0.048), a daily maintenance dose ≥600 mg (HR = 0.3; p = 0.005), and a thyroglobulin reduction ≥60% (HR = 0.4; p = 0.012). The mean daily dose of sorafenib was 666 ± 114 mg, and drug withdrawals due to adverse events (AEs) occurred in 13% of patients. AEs and serious AEs were reported in 93 (95%) and 40 (41%) patients, respectively. The most frequent AE was hand-foot skin reaction (76%)., Conclusions: The PFS of progressive RAI-refractory DTC patients treated with sorafenib was consistent with the findings of the DECISION trial. Disease-related symptoms, lung-only metastasis, a daily maintenance dose, and thyroglobulin reduction were significantly associated with PFS. These results suggest that sorafenib is an effective treatment option for patients with progressive RAI-refractory DTC.