Comparison of TERT and 5-Hydroxymethylcytocine immunohistochemistry in various thyroid carcinomas.

Telomerase reverse transcriptase (TERT) promoter mutation is associated with an aggressive clinical course in thyroid carcinomas. Therefore, detection of TERT promoter mutation is essential for proper patient management. 5-Hydroxymethylcytosine (5hmC) is an epigenetic marker involved in the DNA demethylation pathway, and its loss has been observed in various tumors. Loss of 5hmC has also been reported in thyroid carcinomas and is presented as a possible predictive biomarker for TERT promoter mutation and worse prognosis. This study evaluated the expression of TERT and 5hmC by immunohistochemistry (IHC) in 105 patients (44 in the TERT mutant group and 61 in the TERT wild group) with various thyroid carcinomas. H-scores were calculated using an image analyzer. The median H-scores of TERT IHC were significantly higher in the TERT mutant group than in the TERT wild group (47.15 vs. 9.80). The sensitivity and specificity of TERT IHC for predicting TERT promoter mutations were 65.9 and 65.7 %, respectively. Regardless of TERT promoter mutation status, the 5hmC H-scores were markedly lower in all subtypes of thyroid carcinomas compared to those in their normal counterparts. Significant differences in 5hmC H-scores were observed between N0 and N1 in total thyroid carcinomas, but not within the papillary thyroid carcinoma subgroup. In conclusion, TERT and 5hmC IHC have limitations in predicting the presence of TERT promoter mutations. The expression of 5hmC was downregulated in various thyroid carcinomas compared to that in normal and benign lesions, but comprehensive further studies are required to elucidate the role of 5hmC in thyroid carcinomas.

Limitations of fine-needle aspiration and core needle biopsies in the diagnosis of tall cell variant of papillary thyroid carcinoma.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Prognosis of Patients with 1-4 cm Papillary Thyroid Cancer Who Underwent Lobectomy: Focus on Gross Extrathyroidal Extension Invading Only the Strap Muscles.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Clinical implications of age and excellent response to therapy in patients with high-risk differentiated thyroid carcinoma.

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 < .001; not-ER, p < .001) and DSS (age, p < .001; not-ER, p = .015). Of the 74 patients in the ER group, 7 (9.5%) displayed disease progression and 1 (1.4%) died from DTC. There were no significant differences in PFS and DSS according to age in the ER group. However, older patients had significantly worse PFS and DSS than younger patients in the not-ER group (p = .002 and p < .001, respectively). CONCLUSIONS: Response to therapy classification is important for predicting PFS and DSS in patients with high-risk DTC. Patients in the ER group had a relatively good prognosis, but disease progression occurred in 9.5% of patients. Age was a key predictor of both PFS and DSS in high-risk patients who did not achieve ER.

Prognostic role of the lymphocyte-to-monocyte ratio for clinical outcomes of patients with progressive radioiodine-refractory differentiated thyroid carcinoma treated by sorafenib.

OBJECTIVES: The lymphocyte-to-monocyte ratio (LMR) reflects the status of tumour-infiltrating immune cells and host immunity. The LMR has been reported as a prognostic marker in various cancers. The present study evaluated the role of the LMR as a prognostic marker in patients with progressive radioiodine-refractory (RAIR) differentiated thyroid carcinoma (DTC). DESIGN: Retrospective cohort study. PATIENTS: Forty patients with progressive RAIR DTC who were treated by sorafenib with available baseline complete blood cell count data. MEASUREMENTS: We assessed the response rate, progression-free survival (PFS) and overall survival (OS). RESULTS: The patients were divided into low and high LMR groups based on their baseline LMRs (<4, n = 22, 55% and ≥4, n = 18, 45%, respectively). There were no significant differences in baseline characteristics between the groups. The OS curves differed significantly based on the LMR. The median OS of the low LMR group was 24.3 months and that of the high LMR group was not reached until the end of observation period (P = .015). The PFS curves and median PFS also differed significantly based on the LMR values (P = .019). In multivariate analysis, low LMR was an independent risk factor for all-cause mortality in patients with progressive RAIR DTC (hazard ratio, 2.64; 95% confidence interval: 1.04-6.72, P = .041). CONCLUSION: A low LMR was associated with poor response rate, PFS and OS in patients with progressive RAIR DTC treated with sorafenib. Thus, LMR could be a simple prognostic biomarker in patients with progressive RAIR DTC.

Modified risk stratification based on cervical lymph node metastases following lobectomy for papillary thyroid carcinoma.

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.

The value of preoperative antithyroidperoxidase antibody as a novel predictor of recurrence in papillary thyroid carcinoma.

The link between chronic lymphocytic thyroiditis (CLT) and papillary thyroid carcinoma (PTC) is widely recognized. Considering the strong association between raised antithyroidperoxidase antibody (TPOAb) and CLT, we postulated that the preoperative TPOAb can predict the prognosis of PTC, particularly for recurrence. A total of 2,070 patients who underwent total thyroidectomy for classical type PTC with tumor size ≥1 cm and with available data on preoperative TPOAb and TgAb were enrolled to compare disease-free survival (DFS) according to the presence of preoperative TPOAb, TgAb, and coexistent CLT. Patients with positive preoperative TPOAb had a significantly better DFS compared to patients without positive preoperative TPOAb (hazard ratio (HR) 0.53; 95% confidence interval (CI) 0.30-0.94, p = 0.028) while no difference in DFS was found according to preoperative TgAb status. Positive preoperative TPOAb was an independent prognostic factor for structural persistent/recurrent disease after adjustment for major preoperative risk factors such as age, sex, and tumor size (HR 0.52, 95% CI 0.28-0.99, p = 0.048). Although the coexistence of CLT lowered the risk for structural persistence/recurrence in univariate analysis (HR 0.52, 95% CI 0.31-0.86, p = 0.012), it was not an independent favorable prognostic factor by multivariate analysis (HR 0.65, 95% CI 0.38-1.10, p = 0.106). However, when coexistent CLT was combined with positive preoperative TPOAb, it indicated an independent protective role in structural persistent/recurrent disease (HR 0.39, 95% CI 0.16-0.98, p = 0.045). Our study clearly showed that presence of preoperative TPOAb can be a novel prognostic factor in predicting structural persistence/recurrence of PTC.

Clinical Significance of Gross Invasion of Strap Muscles in Patients With 1- to 4-cm-Sized Papillary Thyroid Carcinoma Undergoing Lobectomy.

BACKGROUND: Given the emerging evidence supporting the lack of prognostic significance of gross extrathyroidal extension invading only strap muscles (strap-gETE), this study investigated whether lobectomy is feasible for patients with strap-gETE. METHODS: A retrospective cohort study was conducted with 636 patients who had 1- to 4-cm-sized papillary thyroid carcinoma (PTC) treated with thyroid lobectomy. Patients with gross invasion of perithyroidal organs other than strap muscles or synchronous distant metastasis were excluded from the study. Disease-free survival (DFS) was compared according to the presence of strap-gETE. RESULTS: Strap-gETE was present in 50 patients (7.9%), with the remaining 586 patients (92.1%) showing no evidence of gETE. During the median follow-up period of 7.4 years, 6% of the patients with strap-gETE and 5.1% of the patients without gETE experienced structural persistent/recurrent disease (p = 0.99). No differences in DFS were observed between the two groups (hazard ratio [HR], 1.24; 95% confidence interval [CI], 0.38-4.08; p = 0.720). After adjustment for five major risk factors (age, gender, tumor size, multifocality, and cervical lymph node metastasis status) in the multivariate analysis, the presence of strap-gETE did not exhibit an independent role in the development of structural persistent/recurrent disease (HR 1.05; 95% CI 0.24-4.53, p = 0.950). CONCLUSIONS: Strap-gETE did not increase the risk of structural persistent/recurrent disease for the patients who underwent lobectomy for 1- to 4-cm-sized PTC. The study data support the limited role of strap-gETE in clinical outcomes and may broaden the indications for lobectomy for patients with PTCs.

Impact of delayed radioiodine therapy in intermediate-/high-risk papillary thyroid carcinoma.

OBJECTIVE: It remains unclear whether the time interval between total thyroidectomy and radioactive iodine therapy (RAIT) affects clinical outcomes in papillary thyroid carcinoma (PTC). Therefore, we evaluated the impact of timing of the first post-thyroidectomy RAIT in intermediate-to-high-risk PTC. DESIGN AND PATIENTS: This retrospective propensity score-matched cohort study included 720 PTC patients who received RAIT for <90 or 90-180 days (early and delayed groups, n = 360 each) after thyroidectomy. Responses to therapy, disease-free survival (DFS) and overall survival (OS) were compared between the two groups. RESULTS: After matching, the baseline characteristics of the 360 patients in each group were similarly adjusted. Within the first 2 years after initial therapy, the number of patients classified into excellent, indeterminate, biochemical incomplete and structural incomplete response categories were 221 (61%), 74 (21%), 39 (11%) and 26 (7%) in the early group, and 204 (57%), 73 (20%), 59 (16%) and 24 (7%) in the delayed group, respectively. There was no significant difference in response to therapy between the two groups (P = 0.183). During the median follow-up of 8.6 years, there was no significant difference in DFS (P = 0.060) and OS (P = 0.400) curves between the two groups. Delayed RAIT was not significantly associated with worse DFS (HR = 1.3, 95% CI 0.9-1.8, P = 0.061) or OS (HR = 1.5, 95% CI 0.6-3.4, P = 0.388). CONCLUSIONS: Delaying the first RAIT until 180 days after total thyroidectomy had no impact on restaging, recurrence and mortality in intermediate-to-high-risk PTC.

Tumour growth rate of follicular thyroid carcinoma is not different from that of follicular adenoma.

OBJECTIVE: Distinguishing malignancy from benign thyroid nodule has always been challenging, especially in follicular lesions. Thyroid nodules with small size and indeterminate cytology do not lead to immediate surgery. We tried to evaluate whether tumour size and tumour growth rate can distinguish follicular thyroid carcinoma (FTC) from follicular adenoma (FA). DESIGN AND PATIENTS: This retrospective study included patients with pathologically proven FTCs (n = 50) and FAs (n = 110) who underwent preoperative serial neck ultrasonography (US) at least 3 times: it comprises 30% of all follicular tumours (32% FAs and 25% FTCs). The growth rates of follicular tumours on serial US were measured using at least 3 consecutive examinations during a median follow-up of 4.1 years (range, 0.7-13.3 years) by experienced radiologists. RESULTS: The FA and FTC groups showed no significant difference in clinicopathological characteristics, including age, proportion of large nodules (>4 cm) and preoperative cytology. The maximum diameter of thyroid nodule was gradually increased in both groups with statistical significance (P < .001 and P < .001, respectively). No significant differences in change of maximum diameter of thyroid nodule (P = .132) and tumour volume (P = .208) were found between the FA and FTC groups during the follow-up. The median time to a significant tumour growth from baseline was not different between the FA and FTC groups (1.4 years and 1.7 years, respectively, P = .556). When we divided the patients into four groups (rapid, moderate, slow and no growth) according to the growth velocity of the thyroid tumours, no significant difference in growth velocity was found among the groups. CONCLUSIONS: The tumour size and growth rate of the thyroid nodule itself could not predict malignancy. Diagnostic approaches that use molecular markers would be more important than clinical features for the decision of diagnostic surgery for patients with follicular tumours.

Serum thyroid-stimulating hormone levels and smoking status: Data from the Korean National Health and Nutrition Examination Survey VI.

OBJECTIVE: We aimed to evaluate differences in serum thyroid-stimulating hormone (TSH) levels according to smoking status and urine iodine concentration (UIC) in a healthy Korean population using data from the Sixth Korean National Health and Nutrition Examination Survey (KNHANES VI). STUDY DESIGN: Sixth Korean National Health and Nutrition Examination Survey (2013-2015) is a nationwide, cross-sectional survey of the Korean population. PATIENTS: Research subjects were selected by two-stage stratified cluster sampling of the population and housing census data. A total of 5639 subjects aged >18 years, who were not pregnant, and had undergone thyroid function testing during the survey period, were included. MEASUREMENT: The level of serum TSH according to smoking status, iodine intake and presence of TPOAb were evaluated. RESULTS: In the reference population, mean serum TSH level in current smokers (1.87 mIU/L, 95% CI, 0.52-5.37 mIU/L) was significantly lower than that in nonsmokers (2.33 mIU/L, 95% CI, 0.79-6.69 mIU/L, P < .001). The rate of thyroperoxidase antibody (TPOAb) positivity was higher in never smoker (7.7%) than past smokers (5.1%) and current smokers (4.7%), but sex-specific rate of TPOAb was not different according to smoking status. The lower serum TSH levels in current smokers were more apparent in iodine-deficient subjects (UIC < 100 µg/L), and this change was diminished in subjects with UICs between 100 and 299 µg/L. The difference in serum TSH levels in current smokers disappeared in subjects with UICs ≥ 300 µg/L. CONCLUSIONS: Smoking is associated with a left-shift in serum TSH level that is more apparent in iodine-deficient subjects. Smoking status is not associated with the presence of TPOAb or iodine intake. The results suggest that smoking has a direct effect on thyroid function that is not mediated by autoimmune processes in the thyroid gland.

Influence of coexistent Hashimoto's thyroiditis on the extent of cervical lymph node dissection and prognosis in papillary thyroid carcinoma.

OBJECTIVE: Previous studies did not focus on the differences in the extent of cervical lymph node (LN) dissection according to coexistent Hashimoto's thyroiditis (HT) in patients with papillary thyroid carcinoma (PTC) and its clinical impact. We aimed to determine whether extensive cervical LN dissection is responsible for favourable clinical outcomes in PTC patients with HT and whether the coexistence of HT itself has an independent protective effect regardless of LN status. DESIGN: Retrospective cohort study. PATIENTS: 1369 patients with PTC who underwent total thyroidectomy with central compartment neck dissection. MEASUREMENTS: Metastatic LN ratio, defined as number of metastatic LNs divided by number of removed LNs, was used to evaluate the extent of LN dissection as well as the status of LN metastasis. Disease-free survival and dynamic risk stratification were compared for clinical outcomes. RESULTS: Presence of HT did not lower the risk of cervical LN metastasis (61.6% in patients with HT vs 65.1% in patients without HT, P = .292). Patients with HT had significantly larger numbers of removed LNs than patients without HT (11 vs 8, respectively, P < .001). Accordingly, metastatic LN ratio was smaller in patients with HT (P = .002), which was independently associated with structural persistent/recurrent disease (hazard ratio [HR] 2.33, 95% confidence interval [CI] 1.30-4.16, P = .004). HT itself was negatively associated with structural persistent/recurrent disease after adjustment for other clinicopathological factors (HR 0.39, 95% CI 0.18-0.87, P = .020). CONCLUSIONS: Coexistence of HT itself is an independent factor associated with favourable outcome in PTC patients, regardless of the extent of LN dissection.

Radiofrequency ablation of primary thyroid carcinoma: efficacy according to the types of thyroid carcinoma.

OBJECTIVE: To evaluate the efficacy of ultrasound (US)-guided radiofrequency ablation (RFA) according to the types of thyroid carcinoma, particularly in patients with a high-surgical risk. MATERIALS AND METHODS: Eight patients with nine tumours of pathologically proven papillary and anaplastic carcinoma were treated by US-guided RFA. Patients with primary thyroid carcinoma were divided into three groups; group (1) Anaplastic carcinoma, group (2) papillary macrocarcinoma, and group (3) papillary microcarcinoma. We evaluated changes in clinical symptoms, tumour volume and local tumour recurrence/metastasis after RFA. Patients were followed up at 1, 6 and 12 months and annually thereafter. RESULTS: Among nine tumours, one anaplastic carcinoma was treated three times and the other anaplastic carcinoma and one papillary macrocarcinoma were treated twice. Group 3 were treated once. The initial mean tumour volume was 107.9 ± 78.6 (with neck bulging), 126.9 (with neck bulging) and 0.16 ± 0.08 mL (without cosmetic or symptomatic problems) in groups 1-3, respectively. Group 1 showed no improvement in clinical symptoms or neck bulging after RFA, whereas group 2 demonstrated a decreased tumour volume measuring 0.7 mL with improved neck bulging. In group 3, mean volume decreased measuring 0.07 ± 0.12 mL. No local tumour recurrence or metastatic lesion was detected during the mean follow-up of 19.3 months in papillary carcinomas. No major complications were encountered. CONCLUSIONS: In patients with primary thyroid carcinoma, RFA achieved excellent local tumour control for papillary macro- and microcarcinoma; however, its clinical effect on anaplastic carcinoma was questionable.

Changes in standardized mortality rates from thyroid cancer in Korea between 1985 and 2015: Analysis of Korean national data.

BACKGROUND: The incidence of thyroid cancer has increased very rapidly in Korea; however, most previous studies suggested that the mortality rate for thyroid cancer remained stable. The objective of the current study was to evaluate recent changes in standardized thyroid cancer mortality using data from Statistics Korea. METHODS: Population and mortality data from 1985 through 2015 were obtained from Statistics Korea. Age-standardized mortality rates (ASMRs) from thyroid cancer per 100,000 population were calculated based on the World Health Organization standard population. RESULTS: In Korea, the ASMRs from thyroid cancer increased from 0.17 (95% confidence interval [CI], 0.17-0.18) per 100,000 in 1985 to 0.85 (95% CI, 0.83-0.86) per 100,000 in 2004, which was the highest among all countries. Subsequently, the ASMRs continuously decreased to 0.42 (95% CI, 0.41-0.43) per 100,000 between 2004 and 2015. The estimated annual percent change (APC) from 1985 to 2004 was 7.94 (95% CI, 6.43-9.46), and the corresponding value from 2004 to 2015 was -4.10 (95% CI, -5.76 to -2.40). Changes in the ASMRs reflected similar patterns in men (1985-2003: APC, 8.51; 2003-2015: APC, -4.32) and women (1985-2004: APC, 7.62; 2004-2015: APC, -4.38) and were also observed in older patients (aged ≥ 55 years). CONCLUSIONS: Thyroid cancer mortality in Korea increased until 2004 and then continuously decreased until 2015. Increases in the early diagnosis of thyroid cancer, changes in exposure to risk factors, and standardization in diagnosis and treatment may be associated with the decrease in thyroid cancer mortality in Korea. Cancer 2017; 123:4808-14. © 2017 American Cancer Society.

Lack of Efficacy of Radioiodine Remnant Ablation for Papillary Thyroid Microcarcinoma: Verification Using Inverse Probability of Treatment Weighting.

BACKGROUND: Most of the increase in thyroid cancer in recent decades has been due to papillary thyroid microcarcinoma (PTMC). We evaluated the efficacy of radioiodine remnant ablation (RRA) in patients with PTMC. METHODS: This historical cohort study included 1932 PTMC patients without lateral cervical lymph node (LN) or distant metastasis who underwent total thyroidectomy (TT) during the median 8.3 years of follow-up. The clinical outcomes of patients with or without RRA were compared using weighted logistic regression models with the inverse probability of treatment weighting (IPTW) method and considering risk factors, including age, sex, primary tumor size, extrathyroidal extension, multifocality, and central cervical LN metastasis. RESULTS: The median primary tumor size of the RRA group was significantly larger than that of the no-RRA group (0.7 vs. 0.5 cm, P < 0.001). There were significantly more patients with multifocality, extrathyroidal extension, and cervical LN metastasis in the RRA group compared with the no-RRA group. There was no significant difference in recurrence-free survival between the two groups (P = 0.11). Cox proportional-hazard analysis with IPTW by adjusting for clinicopathological risk factors demonstrated no significant difference in recurrence of PTMC according to RRA treatment (hazard ratio [HR] 2.02; 95% confidence interval [CI] 0.65-6.25; P = 0.2). CONCLUSIONS: RRA had no therapeutic effect on the clinical outcomes of patients with PTMC who underwent TT. Surgical treatment without RRA could be applicable for patients with PTMC if there is no evidence of lateral cervical LN metastasis or distant metastasis.

Features of papillary thyroid microcarcinoma associated with lateral cervical lymph node metastasis.

OBJECTIVES: Papillary thyroid microcarcinoma (PTMC) has an excellent prognosis with an indolent disease course. However, some PTMCs have an aggressive course with lateral cervical lymph node (LCLN) metastasis or distant metastasis. This study aimed to evaluate the pre-operative features of PTMC associated with LCLN metastasis. DESIGN AND PATIENTS: This retrospective cohort study with a nested, matched case-control design included 199 PTMC patients with LCLN metastasis at initial surgery (N1b group) and 196 PTMC patients without any LN metastasis or persistent disease (N0 NED group) as controls; primary tumour sizes were matched. RESULTS: Compared with the N0 NED group, the N1b group was younger (<50 years) and more likely to be male (P = 0·002 and P = 0·003, respectively). On pre-operative neck ultrasonography (US), N1b group PTMCs were more commonly associated with a location in the upper lobes of the thyroid, or in the subcapsular area and microcalcifications than N0 NED group PTMCs (all P < 0·001). An increase in the number of these features was significantly associated with a higher risk of LCLN metastasis (P < 0·001). Evaluation of the clinical and pre-operative US characteristics of 26 patients with confirmed LCLN recurrence after initial treatment of clinical N0 PTMCs revealed that the distribution of the number of suspicious features in these patients was similar to that of the N1b group. CONCLUSIONS: Papillary thyroid microcarcinomas in young (<50 years) or male patients, with an upper lobe or subcapsular location, and with microcalcification have a higher risk of LCLN metastasis. Individualized management according to the number of these suspicious features may be needed for small thyroid nodules.

Optimal cut-off age in the TNM Staging system of differentiated thyroid cancer: is 55 years better than 45 years?

OBJECTIVE: Age >45 years is included as a variable in the tumor, node, metastases (TNM) staging of differentiated thyroid cancer (DTC), but a higher cut-off value has been suggested to be more clinically relevant and prevent over-staging. We evaluated the optimal age cut-off to predict disease-specific survival (DSS) in patients with DTC. DESIGN AND PATIENTS: This cohort study included 6333 patients with DTC who underwent thyroid surgery at two tertiary referral centres between 1996 and 2005. The optimal age cut-off value between 45 and 65 years for prediction of DSS was assessed. The proportion of variation explained (PVE) and Harrell's c-index was calculated to compare the predictability of each model. RESULTS: The median age of patients was 46·0 years (IQR 37·8-54·6), and 5498 (87%) were female. Median follow-up period was 10·0 years, and 10-year DSS rate was 98%. Using TNM staging with 45 years as the cut-off (TNM45), 10-year DSS rates of stage I-IV were 99·4%, 96·1%, 97·7% and 85·9%, respectively (PVE = 3·0%, Harrell's c-index = 0·693); and using 55 years as the cut-off (TNM55), 99·4%, 92·2%, 95·3% and 79·7%, respectively (PVE = 4·3%, Harrell's c-index = 0·776). On receiver operating characteristic curve analysis, the optimal age cut-off for prediction of DSS was 55·4 years (area under the curve = 0·837, P < 0·001). About 20% of patients were down-staged to stage I using TNM55 compared to that using TNM45. CONCLUSIONS: The cut-off age of 55 years was more appropriate for TNM staging to achieve better predictability for DSS in patients with DTC. This change would prevent over-staging in low-risk patients and prevent over-aggressive treatment.

Preoperative clinicopathological characteristics of patients with solitary encapsulated follicular variants of papillary thyroid carcinomas.

BACKGROUND AND OBJECTIVES: Clinical outcomes in patients with the follicular variant of papillary thyroid carcinoma (FVPTC) tend to vary according to the pathological subtypes. We aimed to evaluate the clinicopathological characteristics including preoperative radiological and cytopathological diagnoses in patients with solitary encapsulated FVPTCs (EFVPTCs) to prove the preoperative assessment dilemma. METHODS: Patients with solitary FVPTCs who underwent thyroid surgery were included. RESULTS: Of 271 patients, 194 patients (72%) had EFVPTCs, whereas 77 patients (28%) had infiltrative FVPTCs (IFVPTCs). EFVPTCs had larger tumor sizes (P < 0.001) and lower frequencies of extrathyroidal extension (P < 0.001) and cervical lymph node (LN) metastasis (P < 0.001) than IFVPTCs. There were significant differences in ultrasonography (US) findings, preoperative cytopathological diagnosis, and the prevalence of BRAF mutations between EFVPTCs and IFVPTCs. Invasive EFVPTCs were diagnosed in 89 patients (33%) and non-invasive EFVPTCs in 105 patients (39%). Non-invasive subtype had smaller tumor sizes (P = 0.001) and lower frequencies of vascular invasion (P = 0.04) and cervical LN metastasis (P = 0.02). There were no significant differences in preoperative US findings and cytopathological diagnoses between invasive and non-invasive EFVPTCs. CONCLUSIONS: Clinicopathological characteristics of EFVPTCs, including preoperative US findings, are different from those of IFVPTCs. However, preoperative radiological and cytopathological findings could not distinguish non-invasive and invasive EFVPTCs.

Myxoid and Sarcomatoid Variants of Adrenocortical Carcinoma: Analysis of Rare Variants in Single Tertiary Care Center.

The aim of this study is to describe rare variants of adrenocortical carcinoma (ACC) and to compare the prognosis with that of conventional ACC. We retrospectively reviewed 8 cases of myxoid variant, 1 sarcomatoid variant, and 14 cases of conventional ACC, who underwent surgical resection at the Asan Medical Center between 1996 and 2014. An analysis of the clinicopathological characteristics, including the Weiss score, Ki-67 labeling index, and reticulin framework assessment is presented. The mean age of patients with myxoid/sarcomatoid ACC was 45 years; 4 out of 9 patients were women. Mean primary tumor size was 12.9 cm and the mean weight was 702.4 g. Seven patients presented in an advanced stage (stage III/IV); 8 of these eventually developed distant metastasis. The mean Weiss score was 5.0 points and the Ki-67 labeling index was 15.6%. The extent of myxoid or sarcomatoid change on histological examination ranged from 10% to 75% of the examined tumor areas; reticulin framework alteration was observed in all cases. Four patients showed venous tumor thrombus. Most of the clinicopathological parameters were not significantly different from those of conventional ACC. However, myxoid or sarcomatoid variant (hazard ratios [HR], 3.59; 95% confidence intervals [CI], 1.13-11.38; P = 0.030) and Ki-67 labeling index (HR, 3.97; 95% CI, 1.18-13.41; P = 0.030) were independent predictors of overall survival after adjusting for age and sex. Myxoid or sarcomatoid histological features or an increased Ki-67 labeling index may be associated with poor overall survival in patients with ACC.