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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Tumor volume (TV) of papillary thyroid carcinoma (PTC) increases exponentially during active surveillance, and the growth rate differs for each patient. TV doubling time (TVDT) is considered a strong dynamic marker for the prediction of the growth rate and progression of the tumor. Methods: This cohort study analyzed 273 PTC patients who underwent active surveillance for more than one year rather than immediate thyroid surgery. TVDT was calculated in each patient, and patients were divided into two groups: rapid-growing (TVDT <5 years) and stable (TVDT ≥5 years). Clinical and initial ultrasonography (US) features between the two groups were compared. Results: The median patient age was 51.1 years (interquartile range [IQR] 42.2–61.0 years), and 76% of the patients were women. The initial TV of PTC was 62.1 mm3 (IQR 28.1–122.8 mm3). During a median of 42 months (IQR 29–61 months) of active surveillance, 10.3% of the patients had a TVDT of less than two years, 5.1% had a TVDT between two and three years, 6.2% had a TVDT between three and four years, 6.6% had a TVDT between four and five years, and 71.8% had a TVDT of five years or more. Patients in the rapid-growing group (77 patients; 28.2%) were significantly younger (p = 0.004) than those in the stable group (196 patients; 71.8%). Being younger than 50 years of age was significantly associated with rapid tumor growth of PTC (odds ratio = 2.31 [confidence interval 1.30–4.31], p = 0.004) in multivariate analysis. In ultrasound findings, macrocalcification was independently associated with rapid tumor growing of PTCs (odds ratio = 4.98 [confidence interval 2.19–11.69], p < 0.001). Conclusions: TVDT is a good indicator for presenting the growing velocity of PTCs during active surveillance. Younger age and macrocalcification in the initial US were associated with rapid-growing PTCs. Determination of TVDT during the early phase of active surveillance may be helpful for the prediction of rapidly progressing PTCs and deciding whether to adopt an early surgical approach. [ABSTRACT FROM AUTHOR]

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. What's new? While chronic lymphocytic thyroiditis (CLT) is generally accepted as a risk factor for papillary thyroid carcinoma (PTC), it is also suspected to protect against PTC recurrence when it coexists with PTC. Our study indicates that coexistent CLT predicts PTC recurrence risk, wherein copositivity for both CLT and preoperative antithyroid peroxidase antibody (TPOAb) is associated with reduced risk of recurrent PTC. In addition, among PTC patients who underwent thyroidectomy, those with preoperative TPOAb positivity had significantly better disease‐free survival than those lacking TPOAb positivity. The findings suggest that preoperative TPOAb and CLT evaluation could help improve accuracy in PTC prognosis. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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). Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: Current guidelines allow lobectomy as treatment for 1–4 cm papillary thyroid carcinomas (PTCs), as previous studies reported no clear survival advantages for total thyroidectomy (TT). However, data on recurrence based on surgical extent are limited. Methods: This study enrolled 2345 patients with 1–4 cm PTC. Those with lateral cervical lymph node metastasis or initial distant metastasis were excluded. Disease-free survival (DFS) was compared after 1:1 propensity score matching by age, sex, tumor size, extrathyroidal extension, multifocality, and cervical lymph node metastasis. Results: Lobectomy was performed in 383 (16.3%) and TT in 1962 (83.7%) patients. In the matched-pair analysis (381 patients in each group), no significant difference in DFS was observed during the median follow-up of 9.8 years (hazard ratio [HR] = 1.35 [confidence interval (CI) 0.40–1.36], p = 0.33). When stratified by tumor size, DFS did not differ between the group with 1–2 cm tumors and that with 2–4 cm tumors (HR = 1.57 [CI 0.75–3.25], p = 0.228; HR = 0.93 [CI 0.30–2.89], p = 0.902, respectively). Multivariate analysis showed that the surgical extent did not play an independent role in structural persistent/recurrent disease development (HR = 1.43 [CI 0.72–2.83], p = 0.306). Conclusion: Patients with 1–4 cm PTCs who underwent lobectomy exhibited DFS rates similar to those who underwent TT after controlling for major prognostic factors. This supports the feasibility of lobectomy as initial surgical approach for these patients and emphasizes that tumor size should not be an absolute indication for TT. [ABSTRACT FROM AUTHOR]

Background: Papillary thyroid cancer (PTC) is a common malignancy diagnosed during pregnancy. However, there is little information on the behavior of PTC during pregnancy. The aim of this study was to evaluate the natural course of PTC in pregnant women. Methods: The study included 19 patients with PTC who delayed thyroid surgery because they were diagnosed with PTC just before or during the early stages of pregnancy. Serial neck ultrasonography (US) was used to evaluate PTCs before surgical treatment and the clinical outcomes after surgery. Results: The median maximal PTC size at initial diagnosis on US was 0.91 cm (interquartile range [IQR] 0.61-1.11), and 13/19 (68.4%) patients had micro-PTCs (≤1 cm). The median maximal PTC size after a median 9.5 months of follow-up was 0.98 cm (IQR 0.72-1.12). There were three (16%) patients who showed a size increase, and five (26%) patients showed a volume increase during the follow-up periods. There was no clinically relevant change in the maximal tumor size during the follow-up period ( p = 0.16). Serial US measurements of PTC size in seven available patients in each trimester showed no significant differences between the different trimesters (first vs. second trimester p = 0.81; second vs. third trimester p = 0.99). No newly developed lesions in the thyroid or cervical lymph nodes were detected by neck US during the follow-up period. Among 19 patients, 16 underwent thyroid surgery after delivery, and the median duration from diagnosis to surgery was 11.9 months. Conclusions: No clinically relevant changes associated with a progression of PTC were observed during pregnancy. Delayed thyroid surgery with active surveillance can be an appropriate approach for pregnant patients with PTC. [ABSTRACT FROM AUTHOR]

Simple Summary: Fine-needle aspiration cytology (FNAC) with measurement of thyroglobulin concentrations obtained through aspiration (FNA-Tg) is routinely used for the diagnosis of metastatic lymph nodes (LNs) from differentiated thyroid carcinomas. However, some areas of uncertainty remain, including the optimal FNA-Tg cutoff and its interpretation based on ultrasound (US) features. In this study, we evaluated the appropriate strategies for interpreting FNAC and FNA-Tg results based on the sonographic features of LNs. We confirmed that the malignancy rate of LNs found to be malignant by FNAC or elevated FNA-Tg was sufficiently high to be diagnosed as metastasis, regardless of the sonographic features. The malignancy rate of LNs with indeterminate or benign FNAC findings and low FNA-Tg were stratified according to their sonographic features. We propose a diagnostic algorithm, based on combined FNAC, FNA-Tg, and US features of LNs, for diagnosing metastatic LNs of differentiated thyroid carcinomas. We aimed to evaluate appropriate strategies for interpreting fine-needle aspiration cytology (FNAC) and thyroglobulin concentrations obtained through aspiration (FNA-Tg) results based on the sonographic features of lymph nodes (LNs). Consecutive patients who underwent ultrasound-guided FNAC and FNA-Tg for metastatic LNs from differentiated thyroid carcinomas (DTCs) from January 2014 to December 2018 were reviewed retrospectively. LNs were categorized sonographically as suspicious, indeterminate, or benign. The optimal FNA-Tg cutoff for metastatic LNs was evaluated preoperatively, after lobectomy, and after total thyroidectomy. The diagnostic performances of FNA-Tg, FNAC, and their combination were analyzed based on the sonographic features of LNs. The malignancy rates of LNs were analyzed based on the sonographic features, FNAC, and FNA-Tg results. Of the 1543 LNs analyzed, 528 were benign, whereas 1015 were malignant. FNA-Tg increased the sensitivity and accuracy of FNAC for LNs. The malignancy rate of LNs found to be malignant by FNAC or elevated FNA-Tg ranged from 82% to 100%, regardless of the sonographic features. The malignancy rate of LNs with indeterminate or benign FNAC findings and low FNA-Tg were stratified according to their sonographic features. We propose a diagnostic algorithm, based on combined FNAC, FNA-Tg, and ultrasound features of LNs, for diagnosing metastatic LNs of DTCs. [ABSTRACT FROM AUTHOR]

Simple Summary: Aggressive variants of papillary thyroid carcinoma (PTC) are associated with unfavorable clinical outcomes. However, limited data exist on the genetic profile of these variants of PTC. We performed targeted next-generation sequencing in 36 tissue samples from patients with aggressive variants of PTC. Aggressive variants of PTC had a higher prevalence of the BRAF mutation and a lower prevalence of RAS mutation than other types of thyroid cancer. The prevalence of mutations in the TERT promoter, TP53, and genes encoding histone methyl transferases (HMTs), switch/sucrose non-fermenting (SWI/SNF) chromatin remodeling complex, and the phosphoinositide 3-kinase/protein kinase B (PKB/AKT)/mammalian target of the rapamycin (PI3K/AKT/mTOR) pathway was between the range of PTCs and poorly differentiated/anaplastic carcinoma from The Cancer Genome Atlas (TCGA) and the Memorial Sloan Kettering Cancer Center (MSKCC) data. Aggressive variants of papillary thyroid carcinoma (PTC) have been described with increasing frequency and are associated with unfavorable clinical outcomes. However, limited data exist on the comprehensive genetic profile of these variants. We performed targeted next-generation sequencing in 36 patients with aggressive variants of PTC and compared it to PTC from The Cancer Genome Atlas (TCGA) project and poorly differentiated thyroid cancers (PDTCs)/anaplastic thyroid cancers (ATCs) from the Memorial Sloan Kettering Cancer Center (MSKCC). BRAF mutation was the most prevalent (89%) in aggressive variants of PTC compared to that in other thyroid cancers. RAS mutation was identified in one patient (3%), which was less frequent than in others. TERT promoter mutation (17%) ranged between that of PTCs (9%) and PDTCs (40%). Tumor suppressor genes, ZFHX3, TP53, and CHEK2, were mutated in 14%, 3%, and 6% of aggressive variants of PTC, respectively. The mutation rate of TP53 (3%) was significantly higher than that of PTCs (0.7%) and lower than that of ATCs (73%). Mutations in three functional groups, histone methyl transferases, SWI/SNF chromatin remodeling complex, and the PI3K/AKT/mTOR pathway, were present in 11%, 14%, and 11% of samples, respectively. In conclusion, aggressive variants of PTC had higher BRAF and lower NRAS mutation prevalence than other thyroid cancers. The prevalence of mutations in the TERT promoter, TP53, and genes encoding three functional groups ranged between that of PTCs and PDTCs/ATCs. [ABSTRACT FROM AUTHOR]

Objectives: Persistence of thyroglobulin antibody (TgAb) in patients with papillary thyroid carcinoma (PTC) years after total thyroidectomy (TT) followed by ablation occurs even without any evidence of structural disease. Few studies have studied the natural course of TgAb positivity and factors that may influence this course. The present study evaluated the time trends of TgAb in ablated PTC patients and aimed to identify the predictive factors for the rate of negative conversion of TgAb.Materials and Methods: Overall, 1279 patients who underwent TT and subsequent ablation for PTC, with available data on thyroid peroxidase Ab (TPOAb) and TgAb prior to surgery (preop-) and ablation (abl-) were enrolled. Patients with initial distant metastasis or recurrence during follow-up were excluded.Results and Conclusion: Preop-TgAb was positive in 24.9% of patients (n = 319), whereas abl-TgAb positivity decreased to 12.8% (n = 164). In 164 patients positive for abl-TgAb, TgAb in patients with higher abl-TgAb levels decreased more gradually than those observed in patients with lower abl-TgAb levels (p < 0.001). Furthermore, in patients within the same range of abl-TgAb levels, patients positive for abl-TPOAb had a higher rate of negative conversion of TgAb compared with negative patients for abl-TPOAb (log rank p < 0.001). TPOAb significantly increased the rate of negative conversion in multivariate analysis adjusted for abl-TgAb (odds ratio 1.59, 95% confidence interval 1.11-2.28, p = 0.011). This study clearly showed that abl-TgAb titers and abl-TPOAb status can predict the rate of negative conversion. These findings can guide the optimal timing for additional examination in patients positive for TgAb during follow-up. [ABSTRACT FROM AUTHOR]

Abstract 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. Highlights • Slit2 inhibits thyroid cancer cell proliferation, migration, and invasion. • The effect is caused by inhibiting transcriptional activity of beta-catenin and regulating Rho GTPase activity. • Loss of Slit2 protein expression is associated with metastasis and recurrence of papillary thyroid cancer. • These findings suggest Slit2 as novel prognostic and potential therapeutic target for thyroid cancer. [ABSTRACT FROM AUTHOR]