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This study was designed to evaluate the prognostic implication of gross extrathyroidal extension (ETE) invading the strap muscles after thyroid lobectomy in patients with 1-4 cm papillary thyroid cancer (PTC).This retrospective cohort study included patients with 1-4 cm PTC who underwent thyroid lobectomy from 2005 to 2012. Overall, 595 patients were enrolled after excluding patients with aggressive variants of PTC, gross ETE into a major neck structure, and lateral cervical lymph node (LN) metastasis. We evaluated the risk factors for structural recurrence after lobectomy in 1-4 cm PTC.Seventy-eight patients (13.1%) had gross ETE invading only the strap muscles. During the median follow-up period of 7.7 years, structural recurrence was confirmed in 35 patients (5.9%). The presence of gross ETE was an independent risk factor for structural recurrence (hazard ratio 2.54, 95% confidence interval 1.19-5.44; p = 0.016). Subgroup analysis of patients with gross ETE showed that 11 and 47 patients had low- and intermediate-risk LN metastasis, respectively. A significant difference in recurrence-free survival was observed according to the degree of cervical LN metastasis (p = 0.03). Those without LN metastasis or low-risk LNs had a 75% lower risk of recurrence when compared with those with both gross ETE and intermediate-risk LNs.Gross ETE and intermediate-risk cervical LN metastasis were associated with a significantly high risk of recurrence after lobectomy in patients with 1-4 cm PTC. Completion thyroidectomy would be considered in this subgroup of patients but not in all patients with gross ETE invading only the strap muscles.

The tall cell variant papillary thyroid carcinoma (TCV-PTC) shows aggressive behaviour. Thus far, the diagnosis of TCV-PTC can only be confirmed using the postoperative specimen. This study aims to evaluate whether fine-needle aspiration (FNA) or core needle biopsy (CNB) could diagnose TCV-PTC preoperatively.This is a retrospective cohort study. We included adult patients diagnosed with TCV-PTC or PTC with tall cell features (TCF) at final surgical pathology between January 2015 and December 2018. Preoperative histology was reviewed for six cytomorphologic features suggesting TCV-PTC in FNA or the percentage of tall cells in the CNB specimen. The postoperative pathology was also reviewed to confirm the percentage of tall cells.A total of 119 patients were included in this study; 35 (29%) patients with PTC with TCF served as controls. The most frequent cytomorphological feature in FNA samples of TCV-PTC was tall columnar cells, including single tombstone-like cells (70%). Among 43 TCV-PTC evaluated by FNA, 3 FNA (7%) revealed the absence of any of the six cytomorphologic features suggesting TCV-PTC. When we defined 30% of tall cells in CNB specimens as a cutoff suggesting TCV-PTC, only 16 (41%) TCV-PTCs could be preoperatively detected, and 3 (7%) TCV-PTCs did not have any tall cells. The proportion of tall cells was not associated with the postoperative percentage of tall cells.Both cytomorphologic features in FNA and the percentage of tall cells in CNB present limitations for use as accurate preoperative diagnostic tools of TCV-PTC.

Active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC) has been accepted worldwide as safe and effective. Despite the growing acceptance of AS in the management of low-risk PTMCs, there are barriers to AS in real clinical settings, and it is important to understand and establish appropriate AS protocol from initial evaluation to follow-up. PTMC management strategies should be decided upon after careful consideration of patient and tumor characteristics by a multidisciplinary team of thyroid cancer specialists. Patients should understand the risks and benefits of AS, participate in decision-making and follow structured monitoring strategies. In this review, we discuss clinical outcomes of AS from previous studies, optimal indications and follow-up strategies for AS, and unresolved questions about AS.

Here, we investigated the potential roles of Mitofusin-2 (MFN2) in thyroid cancer progression. MFN2 regulates mitochondrial fusion/division in cells and plays an important role in various aspects of cell metabolism. MFN2 might involve in cell cycle regulation, apoptosis, and differentiation, and it might play a role as a tumor suppressor in carcinogenesis. We evaluated the prognostic impacts of MFN2 expression in thyroid cancer by analyzing TCGA data. In vitro and in vivo, MFN2 was knocked out using CRISPR/Cas9 or siRNA, and MFN2 was stably overexpressed in two thyroid cancer cell lines (Cal62 and HTH83). TCGA analysis revealed that MFN2 expression was lower in thyroid cancer than in normal tissues and significantly associated with a degree of differentiation, RAS mutations, and less lymph node metastasis. MFN2 expression was significantly correlated with cell adhesion molecules and epithelial to mesenchymal transition (EMT) in a gene-set enrichment assay. MFN2 knock-out (KO) in Cal62 and HTH83 cells using CRISPR/Cas9 or siRNA significantly promoted cell migration and invasion in vitro. The same trends were observed in MFN2 KO mouse embryonic fibroblasts (MEFs) compared to those in the controls (MFN2 WT MEFs). Conversely, MFN2 overexpression in cancer cell lines greatly inhibited cell migration and invasion. However, there was no difference in colony formation and proliferation in Cal62 and HTH83 cells after modulating MFN2, although there were significant differences between MFN KO and WT MEFs. EMT-associated protein expression was induced after MFN2 KO in both cancer cell lines. The mechanistic results suggest that MFN2 might modulate EMT through inducing the AKT signaling pathway. EMT-associated changes in protein expression were also confirmed by modulating MFN2 in xenograft tumors. Thus, MFN2 acts as a tumor suppressor in thyroid cancer progression and metastasis by modulating EMT.

Background: Advanced thyroid cancers, including differentiated thyroid carcinoma (DTC) with distant metastasis, and anaplastic thyroid carcinoma (ATC), are associated with poor clinical outcomes an...

Background: The clinical outcomes of delayed radioiodine remnant ablation (RRA) therapy in patients with low-risk papillary thyroid carcinoma (PTC) are unclear. We aimed to evaluate the clinical impact of the interval between total thyroidectomy (TT) and RRA therapy in patients with low-risk PTC.Methods: We included 526 patients who underwent TT and RRA for low-risk PTC with a primary tumor size of >1 cm between 2000 and 2012. Patients were divided into the early (3 months after TT considering other prognostic factors.

Dabrafenib is a BRAF kinase inhibitor approved for treatment of BRAF-mutated anaplastic thyroid carcinoma (ATC) in combination with trametinib. Erlotinib is a tyrosine kinase inhibitor of EGF receptor (EGFR). We evaluated effects of dabrafenib and erlotinib combination treatment on ATC cells in vitro and in vivo. Cell proliferation, colony formation, apoptosis, and migration of ATC cells harboring a BRAF mutation (BHT101, 8505C, and SW1736) were evaluated after treatment with dabrafenib in combination with erlotinib or trametinib. The changes in activation of mitogen extracellular kinase (MEK) and extracellular signal-related kinase (ERK) signaling were also evaluated by Western blot analysis. Effects of these combinations were also evaluated using an in vivo xenograft model. First, we detected EGFR activation in dabrafenib-resistant SW1736 cells using a phospho-receptor tyrosine kinase array. A dabrafenib and erlotinib combination synergistically inhibited cell proliferation, colony formation, and migration, with an induction of apoptotic cell death in all three ATC cells, compared with dabrafenib or erlotinib alone. This synergistic effect was comparable with a dabrafenib and trametinib combination. The dabrafenib and erlotinib combination effectively inhibited phosphorylated (p)-MEK, p-ERK, and p-EGFR expressions compared with dabrafenib or erlotinib alone, while the dabrafenib and trametinib combination only inhibited p-MEK and p-ERK expressions. The dabrafenib with erlotinib or trametinib combinations also significantly suppressed tumor growth and induced apoptosis in a BHT101 xenograft model. The dabrafenib and erlotinib combination could be a potential novel treatment regimen to overcome drug resistance to dabrafenib alone in patients with BRAF-mutated ATC.

Background The study aimed to compare the prognostic value of the 4th edition of World Health Organization classification (WHO-2017) with the previous WHO classification (WHO-2004) for follicular thyroid carcinoma (FTC). Methods This multicenter retrospective cohort study included 318 patients with FTC from five tertiary centers who underwent thyroid surgery between 1996 and 2009. We evaluated the prognosis of patients with minimally invasive (MI), encapsulated angioinvasive (EA), and widely invasive (WI) FTC according to WHO-2017. Further, we evaluated the proportion of variation explained (PVE) and Harrell's C-index to compare the predictability of disease-free survival (DFS) and disease-specific survival (DSS). Results In total, 227, 58, and 33 patients had MI-, EA-, and WI-FTC, respectively. During a median follow-up of 10.6 years, 46 (14.5%) patients had disease recurrence and 20 (6.3%) patients died from FTC. The 10-year DFS rates of patients with MI-, EA-, and WI-FTC were 91.1%, 78.2%, and 54.9%, respectively (Pl0.001, PVE=7.1%, C-index=0.649). The corresponding 10-year DSS rates were 95.9%, 93.5%, and 73.5%, respectively (Pl0.001, PVE=2.6%, C-index=0.624). The PVE and C-index values were higher using WHO-2017 than using WHO-2004 for the prediction of DFS, but not for DSS. In multivariate analysis, older age (P=0.02), gross extrathyroidal extension (ETE) (P=0.003), and distant metastasis (Pl0.001) were independent risk factors for DSS. Conclusion WHO-2017 improves the predictability of DFS, but not DSS, in patients with FTC. Distant metastasis, gross ETE and older age (≥55 years) were independent risk factors for DSS.

Background Concerns have arisen about the classification of extra-thyroidal extension (ETE) and lateral cervical lymph node metastasis (N1b) in the 8th edition of the tumor-node-metastasis staging system (TNM-8). This study evaluated the prognostic validity of a modified-TNM staging system, focusing on ETE and N1b, in differentiated thyroid carcinoma (DTC) patients. Methods This multicenter retrospective cohort study included 4,878 DTC patients from five tertiary hospitals. In the modified-TNM, T3b in TNM-8 was down-staged to T2, and stage II was subdivided into stages IIA and IIB. Older patients with N1b were reclassified as stage IIB. Results The modified-TNM resulted in staging migration in 540 patients (11%) classified as stage II according to the TNM-8, with 75 (14%), 381 (71%), and 84 patients (16%) classified as stages I, IIA, and IIB, respectively. The 10-year disease-specific survival (DSS) rates in patients classified as stages I, II, III, and IV by TNM-8 were 99.8%, 95.9%, 81.0%, and 41.6%, respectively. The DSS rates of patients classified as stages I, IIA, IIB, III, and IV according to the modified-TNM were 99.8%, 96.4%, 93.3%, 81.0%, and 41.6%, respectively. DSS curves between stages on TNM-8 (P

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 (P = 0.006), but the impact was significant only in patients aged P = 0.004), 2.55 (1.00–6.47; P = 0.049)). For patients aged P for trend = 0.034). In young PTMC patients (

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...

OBJECTIVE Evidence for American Thyroid Association (ATA) risk stratification stems largely from studies involving patients undergoing total thyroidectomy. We aimed to assess the risk of recurrence according to the present ATA risk stratification system in patients who underwent lobectomy. DESIGN Retrospective cohort study. PATIENTS Patients who underwent thyroid lobectomy for 1-4 cm-sized papillary thyroid carcinoma (n = 571). MEASUREMENTS Disease-free survival (DFS) was compared according to the ATA risk stratification, and specific lymph node (LN) characteristics were evaluated to modify the ATA criteria with a higher predictability for recurrence. RESULTS Based on the ATA risk stratification, 439 patients (61.1%) were classified into intermediate- or high-risk group, and consideration for completion thyroidectomy is suggested by ATA guidelines for these patients. However, no significant differences were found in DFS among the low-, intermediate- and high-risk groups (P = .9). In contrast, when patients were stratified according solely to the LN criteria from the ATA risk stratification, only 127 patients (22.2%) had intermediate risk (intermediate-N1a) and exhibited significantly poorer DFS than those with N0 disease (P = .035). Modifying the intermediate-N1a criteria by adding the extranodal extension (ENE) status and omitting the clinical nodal disease enabled the subclassification of 19 patients (3%) with a high risk for recurrence. CONCLUSIONS The present study suggests that risk stratification based solely on LN metastases is more reasonable for predicting structural persistence/recurrence following lobectomy than that based on the overall ATA criteria. Considering the ENE status can assist in selecting patients with a high risk of recurrence to minimize further treatments.

Background: Active surveillance (AS) is recommended as an alternative to immediate surgery in patients with papillary thyroid microcarcinoma (PTMC), but the impact of AS on quality of life has not ...

Background: The lymphocyte-to-monocyte ratio (LMR), which reflects the tumor-infiltrating immune cell status and host immunity, has been reported as a prognostic marker in various cancers. The aim ...

The objective of this study was to evaluate the risk of malignancy (ROM) associated with atypia of undetermined significance (AUS) and suspicious follicular neoplasm (SFN) core needle biopsy (CNB) categories after further sub-classification. Data from 2267 thyroid nodules evaluated by ultrasound-guided CNB, from January to December 2015, were retrospectively reviewed. AUS nodules (n = 556) were sub-classified as follows: (1) architectural atypia (AUS-A; n = 369, 66.4%), (2) cytologic atypia (AUS-C; n = 35, 6.3%), (3) cytologic/architectural atypia (AUS-C/A; n = 85, 15.3%), or (4) oncocytic atypia (AUS-O; n = 67, 12.1%). SFN nodules (n = 172) were sub-classified as follows: (1) architectural atypia only (SFN-A; n = 110, 64%), (2) cytologic/architectural atypia (SFN-C/A; n = 24, 14%), or (3) oncocytic atypia (SFN-O; n = 38, 22%). Diagnostic surgery was performed in 162 (30.2%) AUS cases and 105 (61%) SFN cases. The ROM of each sub-category was evaluated. The overall ROM was 15.3-52.5% in AUS nodules and 35.5-58.1% in SFN nodules. The ROM was higher in the AUS-C (22.9-88.9%) and AUS-C/A (32.9-90.3%) groups than AUS-A (11.9-40%) and AUS-O (7.5-41.7%). In the SFN category, ROM in the SFN-C/A group was also higher than SFN-A or SFN-O (37.5-75%, 40-57.9%, and 21.1-47.1%, respectively). Our study shows that the ROM was higher in AUS or SFN sub-categories with cytologic atypia than those without cytologic atypia. Because of the heterogeneous nature of AUS and SFN categories, sub-classification may be a more effective approach for risk stratification, allowing optimal management of patients with thyroid nodules.

Slits, representative axon guidance molecules, and their Roundabout (Robo) transmembrane receptors play roles in the progression of many cancers. We investigated the effects of Slit2 on the proliferation, migration, and invasion of thyroid cancer cells, and on the prognosis of papillary thyroid cancer (PTC). Slit2 overexpression inhibited the proliferation, migration and invasion of thyroid cancer cells by inhibiting transcriptional activity of beta-catenin and regulating Rho GTPase activity. Slit2 knockdown activated the migration and invasion of thyroid cancer cells and transcriptional activity of beta-catenin. Fragment Slit2 treatment inhibited thyroid cancer cell proliferation in a dose dependent manner, and also inhibited migration and invasion. When we evaluated the protein expression of Slit2 in PTCs, 24 of 160 PTCs (15%) were negative for Slit2 protein expression and these patients had significantly increased risk of cervical lymph node metastasis (P 0.001), distant metastasis (P 0.001) and recurrence of PTC (P 0.001). Our findings suggest a role for Slit2 as a tumor suppressor, and also as a novel prognostic and potential therapeutic target for thyroid cancer.

The concept of a dynamic risk-stratification scheme has been suggested for individualized management of patients with papillary thyroid carcinoma (PTC). However, there is no specified follow-up strategy for patients with an indeterminate response.This study evaluated 403 PTC patients who had an indeterminate response during the first 12-24 months after initial therapy. All patients underwent total thyroidectomy with radioactive iodine remnant ablation. Patients were further classified into three groups based on risk of structural persistence/recurrence: a Tg+ group (detectable thyroglobulin [Tg], regardless of antithyroglobulin antibody [TgAb] or imaging findings; 196 patients), a TgAb+ group (positive results for TgAb with undetectable Tg, regardless of imaging findings; 46 patients), and an Image+ group (nonspecific findings on neck ultrasonography or faint uptake in the thyroid bed on whole-body scan, with undetectable Tg and negative results for TgAb; 161 patients).With a median of 9.6 years (interquartile range 7.7-11.2 years) of follow-up, 56 (14%) PTC patients had structural persistent/recurrent disease: 50 (89%) at locoregional sites and six (11%) at distant sites. The recurrence rate in Tg+, TgAb+, and Image + groups were 26.5%, 8.7%, and 0%, respectively. The median time to detection of structural persistent/recurrent disease from the initial thyroid surgery was 3.7 years (interquartile range 2.5-6.3 years). The optimal cutoff stimulated Tg level to predict structural persistent/recurrent disease was 3.1 ng/mL in the Tg+ group. This classification system revealed higher predictability of structural persistent/recurrent disease than the tumor-node-metastasis staging system and American Thyroid Association risk stratification (proportion of variation explained: 15.7% vs. 2.4% and 0.9%, respectively). Six (3%) patients with distant metastatic disease were all classified in the Tg+ group, and all had lung metastasis.The findings suggest a more individualized follow-up strategy for patients with an indeterminate response. More careful evaluation, including early evaluation of distant metastasis, is necessary in patients with elevated Tg levels. However, for patients testing positive for TgAb or those with only nonspecific imaging findings, regular follow-ups of Tg and TgAb levels and neck ultrasonography are sufficient.

The recently published eighth edition of the American Joint Committee on Cancer (AJCC) staging system has emphasized the importance of gross extrathyroidal extension (gETE) while classifying the tumor (T) stage in differentiated thyroid carcinoma (DTC). However, the clinical impact of gETE invading only the strap muscles or the recurrent laryngeal nerve (RLN) remains unclear due to scarce and conflicting data.A retrospective cohort study was carried out in patients with DTC who underwent thyroid surgery from 1996 to 2005. In total, 3104 patients were included, and disease-specific survival (DSS) was compared according to the degree of gETE, with a median follow-up duration of 10 years.Patients with gETE invading only the strap muscles and with a tumor size ≤4 cm (T3b [≤4 cm]) showed no difference in DSS compared to patients with T2 stage disease (hazard ratio [HR] = 0.81 [confidence interval (CI) 0.24-2.77]; p = 0.737) but rather showed a better DSS than patients with T3a disease (HR = 0.19 [CI 0.05-0.72]; p = 0.014). Conversely, patients with gETE invading to the posterior direction showed significantly poorer DSS than patients with T3 stage disease, even when only the RLN was invaded (HR = 7.78 [CI 3.41-17.75]; p 0.001). However, there was no difference in DSS between gETE invading only the RLN and that invading other posterior organs beyond the RLN (p = 0.563). A modified T classification was suggested to downgrade patients with T3b (≤4 cm) disease to the T2 stage, which revealed higher predictability of survival than the T classification according to the eighth edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (proportion of variation explained: 3.6% vs. 2.65%).gETE invading only the strap muscles did not significantly affect DSS, while that invading the posterior organs significantly affected DSS, even when only the RLN was invaded. The data support the applicability of downgrading patients with T3b (≤4 cm) disease to the T2 stage for a better predictability of survival.

It is unknown whether the growth of thyroid nodules with a Bethesda category III cytology (atypia of undetermined significance [AUS]) is predictive of malignancy, especially in cases with architectural atypia (AUS-A). This study evaluated whether tumor growth rates can help distinguish malignant from benign nodules in the AUS-A subcategory.This retrospective, single-center cohort study included 172 patients who underwent diagnostic thyroid surgery because of a nodule with a cytological diagnosis of AUS-A. The growth kinetics of nodules was assessed by serial preoperative neck ultrasonography over a median follow-up of 52.6 months (range 12.7-198.3 months).Pathologic examinations showed that 112 (65%) and 60 (35%) patients had benign and malignant nodules, respectively. The largest diameter and volume of both benign and malignant nodules increased gradually (p 0.001). However, there was no significant difference in the growth rates of benign and malignant nodules based on the largest diameter (p = 0.132) and volume (p = 0.200). The time to tumor growth curves and estimated median time to significant tumor growth from baseline were not significantly different in malignant nodules compared to benign nodules (p = 0.458 and p = 0.568, respectively). The relative risk (RR) of malignancy of growing and stable nodules did not differ significantly based on the largest diameter (RR = 0.5; p = 0.064) and volume (RR = 0.9; p = 0.748).The size of thyroid nodules classified as AUS-A increased linearly, regardless whether these nodules were benign or malignant. These results suggest that growth kinetics on serial preoperative neck ultrasonography cannot predict malignancy in the AUS-A subcategory.

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.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.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.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.

The diagnosis of encapsulated follicular-patterned thyroid carcinoma (EFPTC) is challenging, and the detection of capsular invasion and/or vascular invasion is essential in distinguishing benign lesions from malignant lesions. In this study, we present a modified transverse-vertical gross examination method with additional vertical cuts at the upper and lower ends of thyroid nodules. In addition, we compared the clinicopathological characteristics of patients with EFPTC between conventional and modified methods. The diagnostic rate of follicular thyroid carcinoma and invasive encapsulated follicular variant of papillary thyroid carcinoma was higher with the modified method (p = 0.003 and p = 0.028, respectively). Furthermore, the paraffin block number and the number of capsular invasion per centimeter were significantly higher with the modified method (p

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.

Active surveillance has been introduced as a management option for low-risk papillary thyroid microcarcinoma (PTMC) due to its mostly indolent course.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.Patients' age at diagnosis was 51 ± 12 years, and 110 (30%) patients were45 years of age. The initial maximum diameter and volume of PTMCs were 5.9 ± 1.7 mm and 81.0 ± 77.7 mmA 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.

BACKGROUND Patients with American Thyroid Association (ATA) high-risk differentiated thyroid carcinoma (DTC) have poor clinical outcomes. This study aimed to evaluate the clinical implications of age and response to therapy classification in patients with ATA high-risk DTC. DESIGN AND PATIENTS This study included 222 patients with high-risk DTC who initially underwent therapy between 2000 and 2010 in a single tertiary center in Korea. We evaluated the prognostic parameters associated with progression-free survival (PFS) and disease-specific survival (DSS) with a focus on age and achieving an excellent response (ER). RESULTS During the median follow-up period of 11.3 years, disease progression was detected in 77 patients (34.7%), and disease-specific mortality was reported in 31 patients (14.0%). Older age (≥55 years) and not achieving ER (not-ER) were independent risk factors associated with PFS (age, p

Background: Serum calcitonin measurement contains various clinical and methodological aspects. Its reference level is wide and unclear despite sensitive calcitonin kits are available. This study aimed to identify the specific reference range in the healthy Korean adults.Methods: Subjects were ≥20 years with available calcitonin (measured by a two-site immunoradiometric assay) data by a routine health checkup. Three groups were defined as all eligible subjects (group 1, n=10,566); subjects without self or family history of thyroid disease (group 2, n=5,152); and subjects without chronic kidney disease, autoimmune thyroid disease, medication of proton pump inhibitor/H2 blocker/steroid, or other malignancies (group 3, n=4,638).Results: This study included 6,341 male and 4,225 female subjects. Males had higher mean calcitonin than females (2.3 pg/mL vs. 1.9 pg/mL, P

Background: Active surveillance is recommended as an alternative to immediate surgery for low-risk papillary thyroid microcarcinoma (PTMC), and determining meaningful changes in diameter and volume...

Background: We examined the changes in glucose metabolites of papillary thyroid cancer (PTC) and identified phosphoglycerate dehydrogenase (PHGDH) as a potential target. The role of PHGDH in the proliferation and tumorigenesis of thyroid cancer cells and its clinical significance were analyzed. Methods: Glucose metabolites of various thyroid tissues were analyzed via targeted metabolomics analysis. In vitro experiments using shPHGDHs, inhibitor (NCT503), or PHGDH overexpression in thyroid cell lines (BCPAP, 8505C, and Nthy-Ori) were performed. In vivo experiments were performed by using shPHGDH. Human tissue samples and The Cancer Genome Atlas (TCGA) data were used to validate the experimental findings. Results: PHGDH knockdown in BCPAP and 8505c cell lines significantly inhibited cell viability, colony formation, and tumor spheroid formation compared with the control. In addition, treatment with NCT503 showed similar results. PHGDH inhibition by both knockdown and treatment with NCT503 significantly inhibited the expression of embryonic cancer stemness markers (Oct4, Sox2, KLF4, and Nanog). PHGDH overexpression in Nthy-Ori cells significantly increased cell viability and colony formation. The stemness markers were significantly increased after PHGDH overexpression. PHGDH knockdown significantly inhibited tumor growth in an in vivo mouse xenograft study using 8505c cells. The protein expression of Oct4 in tumors was significantly reduced after PHGDH knockdown. The associations between PHGDH expression and stemness markers were confirmed in the TCGA data and human thyroid tissue samples. Positive PHGDH protein expression was associated with metastases of PTC. Conclusions: PHGDH expression is induced in thyroid cancer and is associated with stemness and aggressiveness of PTC.

We aimed to evaluate the clinical efficacy and safety of lenvatinib in patients with advanced anaplastic thyroid cancer (ATC) in real-world practice. This multicenter, retrospective cohort study included 14 patients with advanced ATC who received lenvatinib. We evaluated the response rate according to RECIST. Ten patients had de novo ATC, and lenvatinib was used as a neoadjuvant treatment in eight patients. During a median follow-up of 6.7 months, patients received lenvatinib at a median dose of 13 mg daily. Overall, four patients (29%) showed partial response, nine (64%) had stable disease, and one (7%) had progressive disease. Tumor burden was reduced in 13 patients (93%), and the median best percent change from the baseline was −15.8%. The median progression-free survival and overall survival were 5.7 months (95% confidence interval [CI], 2.2–8.3) and 6.7 months (95% CI, 3.0–8.4), respectively. All patients experienced adverse events (AEs). Most AEs were manageable but two AEs—tracheal perforation, and pneumothorax and pneumomediastinum—were life-threatening. One patient underwent flap surgery for reconstruction of their tracheal perforation, and another died of pneumothorax and pneumomediastinum, which seemed to be related to lenvatinib. In this multicenter real-world study, lenvatinib demonstrated limited clinical activity in advanced ATC. It effectively reduced the tumor burden but showed doubtful survival benefit. Although most AEs were manageable, one fatal AE was related to rapid tumor shrinkage. Further studies are needed to clarify the efficacy and optimal dose of lenvatinib in patients with advanced ATC.

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.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.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%.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.

Objective Evidence for unfavorable outcomes of each type of aggressive variant papillary thyroid carcinoma (AV-PTC) is not clear because most previous studies are focused on tall cell variant (TCV) and did not control for other major confounding factors contributing to clinical outcomes. Design Retrospective cohort study. Methods This study included 763 patients with classical PTC (cPTC) and 144 with AV-PTC, including TCV, columnar cell variant (CCV) and hobnail variants. Disease-free survival (DFS) and dynamic risk stratification (DRS) were compared after two-to-one propensity score matching by age, sex, tumor size, lymph node metastasis and extrathyroidal extension. Results The AV-PTC group had significantly lower DFS rates than its matched cPTC group (HR = 2.16, 95% CI: 1.12–4.16, P = 0.018). When TCV and CCV were evaluated separately, there was no significant differences in DFS and DRS between patients with TCV (n = 121) and matched cPTC. However, CCV group (n = 18) had significantly poorer DFS than matched cPTC group (HR = 12.19, 95% CI: 2.11–70.33, P = 0.005). In DRS, there were significantly more patients with structural incomplete responses in CCV group compared by matched cPTC group (P = 0.047). CCV was an independent risk factor for structural persistent/recurrent disease in multivariate analysis (HR = 4.28; 95% CI: 1.66–11.00, P = 0.001). Conclusions When other clinicopathological factors were similar, patients with TCV did not exhibit unfavorable clinical outcome, whereas those with CCV had significantly poorer clinical outcome. Individualized therapeutic approach might be necessary for each type of AV-PTCs.