Outcome Of Papillary Thyroid Cancer Research Articles

Analysis of delayed initial radioactive iodine therapy and clinical outcomes in papillary thyroid cancer: a two-center retrospective study.

It remains unclear whether the time interval between total thyroidectomy and radioactive iodine (RAI) therapy influences clinical outcomes in papillary thyroid carcinoma (PTC). This study aims to evaluate the impact of the timing to initiate RAI therapy on the response in PTC patients. We retrospectively included 405 patients who underwent total thyroidectomy and subsequent RAI therapy at two tertiary hospitals in southwest China. Patients were categorized into two groups based on the interval between thyroidectomy and initial RAI therapy, that is, an early group (interval ≤90 days, n = 317) and a delayed group (interval >90 days, n = 88). Responses to RAI therapy were classified as excellent, indeterminate, biochemical incomplete, or structural incomplete. Univariate and multivariate analyses were conducted to identify factors associated with a nonexcellent response. Excellent responses were observed in 77.3% of the early group and 83.0% of the delayed group (P = 0.252). No significant impact of RAI therapy timing was also observed across all American Thyroid Association risk classification categories. These findings persisted when patients were analyzed separately according to RAI dose (intermediate-dose group: 3.7 GBq [n = 332]; high-activity group: ≥5.5 GBq [n = 73]), further subdivided by the timing of RAI therapy. Multivariate analysis identified lymph node dissection, RAI dose, and stimulated thyroglobulin as independent risk factors for excellent response (P < 0.05). The timing of initial RAI therapy following surgery did not significantly affect outcomes in patients with PTC.

Risk stratification by combining common genetic mutations and TERT promoter methylation in papillary thyroid cancer.

Risk stratification based on somatic mutations in TERT promoter and BRAF/RAS has been well established for papillary thyroid cancer (PTC), and there is emerging evidence showed that TERT promoter methylation was frequently observed in thyroid cancer patients with adverse features. This study was aimed to comprehensive explore the prognostic value of BRAF/RAS mutations, TERT promoter mutations, and TERT promoter methylation in PTC. The relationships of BRAF/RAS mutations, TERT promoter mutations, and TERT promoter methylation with clinical characteristics and outcomes of PTC were analyzed in 382 patients with PTC. TERT promoter mutation and hypermethylation were collectively observed in 52 (13.6%) samples and associated with BRAF/RAS mutation, aggressive clinical characteristics, and poor clinical outcomes of PTC. Coexistence of BRAF/RAS and TERT alterations was found in 45 of 382 (11.8%) PTC patients and strongly associated with old patient age, extrathyroidal extension, advanced pathologic T stage and metastasis. Importantly, patients with both BRAF/RAS and TERT alterations had higher rates of tumor recurrence (13.6% vs 1.5%, P = 0.042) and disease progression (24.4% vs 3.3%, P < 0.001) than patients without any alterations, and cox regression analysis revealed that the coexistence of BRAF/RAS and TERT alterations, but not BRAF/RAS or TERT alterations alone, increased the risk of progression-free interval with an adjusted HR of 10.35 (95% CI: 1.79-59.81, P = 0.009). This study suggested that comprehensively analysis of BRAF/RAS mutations, TERT promoter mutation and methylation is an effective strategy to identify high-risk patients with PTC.

TERT promoter methylation is associated with high expression of TERT and poor prognosis in papillary thyroid cancer.

The telomerase reverse transcriptase (TERT) is overexpressed and associated with poor prognosis in papillary thyroid cancer (PTC), the most common subtype of thyroid cancer. The overexpression of TERT in PTC was partially attributed to transcriptional activation by two hotspot mutations in the core promoter region of this gene. As one of the major epigenetic mechanisms of gene expression regulation, DNA methylation has been proved to regulate several tumor-related genes in PTC. However, the association of TERT promoter DNA methylation with TERT expression and PTC progression is still unclear. By treating PTC cell lines with demethylating agent decitabine, we found that the TERT promoter methylation and the genes' expression were remarkably decreased. Consistently, PTC patients with TERT hypermethylation had significantly higher TERT expression than patients with TERT hypomethylation. Moreover, TERT hypermethylated patients showed significant higher rates of poor clinical outcomes than patients with TERT hypomethylation. Results from the cox regression analysis showed that the hazard ratios (HRs) of TERT hypermethylation for overall survival, disease-specific survival, disease-free interval (DFI) and progression-free interval (PFI) were 4.81 (95% CI, 1.61-14.41), 8.28 (95% CI, 2.14-32.13), 3.56 (95% CI, 1.24-10.17) and 3.32 (95% CI, 1.64-6.71), respectively. The HRs for DFI and PFI remained significant after adjustment for clinical risk factors. These data suggest that promoter DNA methylation upregulates TERT expression and associates with poor clinical outcomes of PTC, thus holds the potential to be a valuable prognostic marker for PTC risk stratification.

Delayed Surgery for and Outcomes of Papillary Thyroid Cancer: Is the Pendulum Still Swinging?

Clinical ThyroidologyVol. 35, No. 5 Thyroid CancerDelayed Surgery for and Outcomes of Papillary Thyroid Cancer: Is the Pendulum Still Swinging?Giorgio GraniGiorgio GraniDepartment of Translational and Precision Medicine, Sapienza University of Rome, Rome, ItalySearch for more papers by this authorPublished Online:12 May 2023https://doi.org/10.1089/ct.2023;35.192-194AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetails Volume 35Issue 5May 2023 Information© Copyright 2023, Mary Ann Liebert, Inc.To cite this article:Giorgio Grani.Delayed Surgery for and Outcomes of Papillary Thyroid Cancer: Is the Pendulum Still Swinging?.Clinical Thyroidology.May 2023.192-194.http://doi.org/10.1089/ct.2023;35.192-194Published in Volume: 35 Issue 5: May 12, 2023PDF download

HIF1A overexpression predicts the high lymph node metastasis risk and indicates a poor prognosis in papillary thyroid cancer

ObjectiveTo investigate the value of Hypoxia-inducible factor 1 A (HIF1A) in predicting lymph node metastasis (LNM) stage and clinical outcomes of papillary thyroid cancer (PTC) patients. Materials and methodsThe HIF1A gene expression analysis in PTC was performed by bioinformatics approaches followed by evaluating its protein level using immunohistochemistry analysis. The role of HIF1A in predicting the LNM stage was evaluated by logistic regression analysis, nomogram construction, and receiver operating characteristic (ROC) analysis. We performed survival analyses to determine its prognostic value. Enrichment analysis was conducted, and immune cell infiltration and stromal content were evaluated to examine the underlying mechanism of HIF1A in PTC. ResultsHIF1A transcription and protein levels were significantly high in PTC tissue (P < 0.05). Its overexpression predicted high LNM risk and unfavorable prognosis for PTC patients (P < 0.05). Cox regression analysis revealed HIF1A as an independent prognostic biomarker for the disease-free interval (DFI) (P < 0.01). In addition, HIF1A was positively related to tumor-suppressive immunity but was negatively correlated with anti-tumor immunity. HIF1A upregulation was also associated with increased stromal content. ConclusionsHIF1A overexpression is an independent predictor for worse DFI in PTC. The HIF1A expression may affect the prognosis of PTC patients through immune- and stroma-related pathways. Our study provides new insight into the role of HIF1A in PTC biology and clinical management.

Preoperative voice analysis and survival outcomes in papillary thyroid cancer with recurrent laryngeal nerve invasion.

To investigate the clinicopathological characteristics of papillary thyroid cancer (PTC) and identify risk factors for postoperative recurrence of PTC with recurrent laryngeal nerve (RLN) involvement. In total, 171 patients (112 women and 59 men, age: 18-80 years, and 65 patients aged ≥ 55) with T4a PTC with RLN involvement, treated at Beijing Tongren Hospital, Capital Medical University, from January 2006 to December 2020, were retrospectively examined. Clinicopathological characteristics, including voice analysis results, and survival outcomes were assessed. The Mann-Whitney U and Kruskal-Wallis H tests were used to analyze differences in acoustic parameters. The Kaplan-Meier method was used to calculate the overall survival (OS) and recurrence-free (RFS) rates. Univariate and multivariate Cox regression analyses were performed of the clinical data. The postoperative follow-up period ranged from 12 to 196 months (mean: 66.18 months). Of the 171 patients, 16 had recurrence and 8 died of thyroid-related diseases. The 5-year OS rate was 95.22%. The 5-year RFS rate was 89.38%. Jitter and shimmer were higher and maximum phonation time was shorter in patients with preoperative vocal cord paralysis (VCP) than in those without RLN involvement, and in those with RLN involvement but without preoperative VCP. Acoustic parameters were similar in patients with no preoperative VCP and those without RLN involvement. Voice analysis results did not differ between cases with RLN adhesion and RLN invasion. Univariate analysis showed that age at onset ≥ 55 years, preoperative RLN palsy, and esophageal invasion were risk factors for postoperative recurrence of PTC with RLN involvement. Multivariate analysis showed that onset age ≥ 55 years (OR 4.52, 95% confidence interval: 1.44-14.19, P = 0.010) was an independent risk factor for recurrence. PTC patients with RLN invasion can achieve good outcomes. Preoperative voice analysis may offer insights into RLN function. Age of onset ≥ 55 years is an independent risk factor for postoperative recurrence in T4a PTC patients.

Based on different immune responses under the glucose metabolizing type of papillary thyroid cancer and the response to anti-PD-1 therapy.

Glucose metabolism-related genes play an important role in the development and immunotherapy of many tumours, but their role in thyroid cancer is ambiguous. To investigate the role of glucose metabolism-related genes in the development of papillary thyroid cancer (PTC) and their correlation with the clinical outcome of PTC, we collected transcriptomic data from 501 PTC patients in the Cancer Genome Atlas (TCGA). We performed nonnegative matrix decomposition clustering of 2752 glucose metabolism-related genes from transcriptome data and classified PTC patients into three subgroups (C1 for high activation of glucose metabolism, C2 for low activation of glucose metabolism and C3 for moderate activation of glucose metabolism) based on the activation of different glucose metabolism-related genes in 10 glucose metabolism-related pathways. We found a positive correlation between the activation level of glucose metabolism and the tumour mutation burden (TMB), neoantigen number, mRNA stemness index (mRNAsi), age, and tumour stage in PTC patients. Next, we constructed a prognostic prediction model for PTC using six glucose metabolism-related genes (PGBD5, TPO, IGFBPL1, TMEM171, SOD3, TDRD9) and constructed a nomogram based on the risk score and clinical parameters of PTC patients. Both the prognostic risk prediction model and nomogram had high stability and accuracy for predicting the progression-free interval (PFI) in PTC patients. Patients were then divided into high-risk and low-risk groups by risk score. The high-risk group was sensitive to paclitaxel and anti-PD-1 treatment, and the low-risk group was sensitive to sorafenib treatment. We found that the high-risk group was enriched in inflammatory response pathways and associated with high level of immune cell infiltration. To verify the accuracy of the prognostic prediction model, we knocked down PGBD5 in PTC cells and found that the proliferation ability of PTC cells was significantly reduced. This suggests that PGBD5 may be a relatively important oncogene in PTC. Our study constructed a prognostic prediction model and classification of PTC by glucose metabolism-related genes, which provides a new perspective on the role of glucose metabolism in the development and immune microenvironment of PTC and in guiding chemotherapy, targeted therapy and immune checkpoint blockade therapy of PTC.

Hashimoto's thyroiditis on outcomes in papillary thyroid cancer revisited: experience from South East Asia.

The association between Hashimoto Thyroiditis (HT) and papillary thyroid cancer (PTC) remains uncertain. HT, the most common inflammatory condition of the thyroid, is postulated to increase the risk of PTC and yet confer cancer-retarding effects. In this study, we aim to evaluate the prevalence of HT in patients surgically treated for PTC and evaluate the long-term prognostic implications. This is a retrospective study of 521 patients with PTC who underwent hemi- or total thyroidectomy between January 2000 and December 2018 at a tertiary referral centre. Patients were categorised into two group: group A (n=402) consists of patients with PTC without HT, whereas group B (n=119) consists of patients with PTC and HT. Demographic and clinicopathological details, recurrence rates and overall survival were collected. Univariate and multivariate analyses were performed to evaluate for clinical factors associated with HT. A total of 521 patients with a mean age of 46.7 years were evaluated. HT was detected in 22.8% of patients with PTC. On multivariate analysis, presence of HT was associated with a lower incidence of extrathyroidal extension (hazard ratio: 0.59, 95%confidence interval 0.37-0.95). Also, patients with HT tend to have fewer cycles of radioactive iodine and correspondingly have excellent response to treatment. However, no differences in recurrence rates and overall survival were detected. One-fifth of patients with PTC have coexisting HT. These patients tend to have less-aggressive tumour features such as extrathyroidal extension. However, the effect of HT on recurrence and overall survival appears to be inconsequential clinically.

Potential Impact of Body Mass Index on the Clinical Outcome of Papillary Thyroid Cancer After High-Dose Radioactive Iodine Therapy.

ContextObesity has been reported as a potential risk factor for the aggressiveness of papillary thyroid cancer (PTC), but the data gathered so far are conflicting.ObjectiveThe aim of our study was to evaluate the relationship between body mass index (BMI) and aggressiveness of PTC at the diagnosis and clinical outcome.MethodsA total of 337 patients who underwent radioactive iodine (RAI) therapy between March 2017 and May 2020 were recruited. Patients were divided into four groups: underweight (BMI<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (BMI≥ 30 kg/m2). Treatment and follow-up were defined according to criteria used in the 2015 ATA guidelines.ResultsThis study included 337 patients with PTC (71.5% women, median age 45.21 ± 13.04 years). The mean BMI was 24.2 ± 3.1 kg/m2. Obese groups had a higher age than the other groups (P = 0.001). Moreover, obese patients had larger tumor sizes and higher T stage, compared to overweight, normal weight, and underweight patients (P = 0.007). After a median follow-up of 32 months, 279 patients (82.7%) had achieved an excellent response (ER) to therapy. The overall ER rates were compared between groups, and they did not differ significantly.ConclusionsWe demonstrated that BMI may have an additive effect on the aggressiveness of PTC, but did not have an effect on the response to therapy after high-dose RAI therapy.

Long-Term Oncological Outcomes of Papillary Thyroid Cancer and Follicular Thyroid Cancer in Children: A Nationwide Population-Based Study

IntroductionPediatric thyroid carcinoma is a rare malignancy and data on long-term oncological outcomes are sparse. The aim of this study was to describe the long-term oncological outcomes of pediatric papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) in a national cohort, and to identify risk factors for recurrence.MethodsWe conducted a nationwide, retrospective cohort study, in which we combined two national databases. Patients aged <18 years, diagnosed with PTC or FTC in the Netherlands between 2000 and 2016, were included. pT-stage, pN-stage, multifocality and angioinvasion were included in a Cox-regression analysis for the identification of risk factors for recurrence.Results133 patients were included: 110 with PTC and 23 with FTC. Patients with PTC most often presented with pT2 tumors (24%) and pN1b (45%). During a median follow-up of 11.3 years, 21 patients with PTC developed a recurrence (19%). Nineteen recurrences were regional (91%) and 2 were pulmonary (9%). No risk factors for recurrence could be determined. One patient who developed pulmonary recurrence died two years later. Cause of death was not captured. Patients with FTC most often presented with pT2 tumors (57%). One patient presented with pN1b (4%). In 70%, no lymph nodes were collected. None of the patients with FTC developed a recurrence or died.ConclusionPediatric PTC and FTC are two distinct diseases. Recurrence in pediatric PTC is common, but in FTC it is not. Survival for both pediatric PTC and FTC is very good.

The genetic duet of BRAF V600E and TERT promoter mutations predicts the poor curative effect of radioiodine therapy in papillary thyroid cancer.

The BRAF V600E and TERT promoter mutations are well known to be associated with poor clinical outcomes of papillary thyroid cancer (PTC). Radioactive iodide (RAI)-refractory can be evaluated in advance of treatment, for which predictive biomarkers may be helpful. The present study is to analyze the correlation of both mutations with the curative effect of radioiodine therapy. A total of 126 patients who underwent RAI therapy from October 2016 to August 2019 were recruited. Treatment and follow-up were defined according to criteria used in the 2015 ATA guidelines. The RAI response of patients was assessed as excellent response (ER) and RAI-refractory at the end of follow-up. When dividing the 126 patients into 4 groups, the no mutation, only BRAF V600E mutation, only TERT promoter mutation, and coexistence of two mutation groups were found in 15.8%, 68.3%, 2.4%, and 13.5% patients. RAI-refractory was found in 52.9% (9/17) patients with the coexisting BRAF and TERT mutations. In logistic regression analysis, M1, BRAF, and TERT mutation were confirmed to be independent factors predicting the RAI-refractory. Moreover, 35.3%, 41.2%, and 23.5% of patients in the BRAF and TERT mutation group were assessed as ER, SIR, and BIR respectively. Kaplan-Meier analyses revealed that the genetic duet of BRAF V600E and TERT promoter mutations was associated with a lower ER reached time. We found that BRAF V600E and TERT promoter mutation is significantly correlated with the poor curative effect of RAI therapy in PTC. ClinicalTrials.gov Identifier: ChiCTR1800018760.

Prevalence of Hashimoto Thyroiditis in Adults With Papillary Thyroid Cancer and Its Association With Cancer Recurrence and Outcomes

Hashimoto thyroiditis (HT) has been suggested to be associated with papillary thyroid cancer (PTC) development. However, its association with PTC progression remains unclear. To examine the association between HT and PTC presentation and outcomes. This retrospective cohort study included a review of patients aged 18 to 75 years who had pathologically confirmed PTC treated at a single center in China from January 1, 2001, to December 31, 2014. Data analysis was performed from November 1 to December 31, 2020. Coexistent HT was defined according to evaluation of postoperative paraffin sections. The primary outcome was the association of HT with PTC-related mortality, assessed using Cox proportional hazards regression models. The secondary outcome was the association of HT with aggressive characteristics and structural recurrence of PTC, assessed using logistic regression and Cox proportional hazards regression with and without adjustment for related factors. Of 9210 patients with PTC (mean [SD] age, 43.6 [12.0] years; 6872 [75%] women) included in the analysis, 1751 (19%) had HT. In the logistic regression model, HT was negatively associated with frequencies of primary tumor size of 4 cm or greater (adjusted odds ratio [aOR], 0.20; 95% CI, 0.12-0.33; P < .001), gross extrathyroidal extension (aOR, 0.44; 95% CI, 0.36-0.54; P < .001), extranodal extension (aOR, 0.66; 95% CI, 0.55-0.80; P < .001), and distant metastasis (aOR, 0.17; 95% CI, 0.04-0.71; P = .02). After a median follow-up of 85 months (range, 12-144 months), 131 PTC-related deaths were identified in the cohort; 2 patients who died had HT. Patients with HT had significantly superior outcomes compared with patients without HT in terms of unadjusted 10-year disease-specific survival (99.9% vs 96.6%; log-rank P < .001) and recurrence-free survival (92.0% vs 87.6%; log-rank P = .001). After adjusting for sex, age, primary tumor size, extrathyroidal extension, lymph node metastasis, distant metastasis, extent of surgery, and radioactive iodine ablation, HT was associated with decreased PTC-related mortality (hazard ratio [HR], 0.19; 95% CI, 0.05-0.76; P = .02). Stratified analysis showed that HT was associated with less frequent structural recurrence in patients with extrathyroidal extension (HR, 0.52; 95% CI, 0.38-0.71; P < .001; P = .002 for interaction) or after total thyroidectomy (HR, 0.50; 95% CI, 0.35-0.69; P < .001; P = .009 for interaction). In this cohort study, patients with coexistent HT had less aggressive characteristics at presentation and better outcomes of PTC than did patients without HT. The findings suggest that autoimmune thyroiditis has a protective role in association with thyroid cancer.

Recurrence Factors and Characteristic Trends of Papillary Thyroid Cancer over Three Decades.

Background The prevalence of thyroid cancer is rising worldwide. Although thyroid cancer has a favorable prognosis, up to 20% of patients experienced recurrent disease during the follow-up period. The present study aimed to examine the trend of incidence and factors associated with recurrence and outcomes of papillary thyroid cancer (PTC) in Thai patients over the last 30 years. Methods We reviewed the clinical data of all patients with PTC who were treated between 1987 and 2019 at Theptarin Hospital. Clinical characteristics, epidemic trend, factors associated with the persistence/recurrence of the disease, overall disease-specific survival rate, and overall disease-free survival rate were analysed. Results A total of 235 patients with PTC who were registered between 1987 and 2019 were reviewed. The mean age was 42.5 ± 14.3 years, with a mean follow-up of 9.5 years. Papillary thyroid microcarcinoma (PTMC) was consistently increased and accounted for 21.4% (50/235) of total cases. The American Thyroid Association (ATA) risk stratification was high in 24% of all PTMCs in the last decade, and 16.0% of these patients experienced local recurrence during the follow-up period. Coexistence with Hashimoto's thyroiditis (HT) was found in one-fifth of the patients with PTC and was correlated with a low recurrence rate (HR: 0.16, P=0.013). Only age ≥55 years associated with the persistence/recurrence of the disease. The overall disease-free survival and disease-specific survival rates were 77.4% and 98.3%, respectively. Conclusions The prognosis of PTC is generally considered favorable. However, approximately one-fourth of patients with PTMC demonstrated more aggressive clinical behavior, particularly in the last decade of the study. Coexistence of HT contributed to a better prognosis.

Recurrence Factors and Characteristic Trends of Papillary Thyroid Cancer Over Three Decades

Abstract Background: The prevalence of thyroid cancer is rising worldwide. Although thyroid cancer has a favorable prognosis, up to 20% of patients experienced recurrent disease at some point during follow-up. The present study aimed to examine the recurrent factors that determined the outcomes of papillary thyroid cancer (PTC) and the characteristic trends in Thai patients over the last 30 years in a single institute. Methods: We reviewed the clinical data of all patients with PTC who were treated between 1987 and 2019. Clinical characteristics, epidemic trends, factors associated with the persistent or recurrent disease, disease-specific survival rate and disease-free survival rate were analysed. Results: A total of 235 patients with PTC who were registered between 1987 and 2019 were reviewed. The mean age was 41.0 ± 14.3 years, with a mean follow-up of 113 months. Papillary thyroid microcarcinoma (PTMC) was consistently increased and accounted for 21.4% (50/235) of total cases. According to American Thyroid Association (ATA) risk stratification, high ATA risk was found 24% of all PTMCs in the last decade, and 16.7% of these patients experienced local recurrence during the follow-up period. Coexistence with Hashimoto’s thyroiditis (HT) was found in one-fifth of the patients with PTC and was correlated with a low recurrent rate (HR 0.21, p = 0.009). Factors associated with the persistent or recurrent of disease included age &amp;gt; 55 years and high ATA risk. The overall disease-free survival rate and disease-specific survival rate were 77.4% and 98.3%, respectively. Conclusions: The prognosis of PTC is generally considered favorable. However, more than one-third of patients with PTMC demonstrated more aggressive clinical behavior, particularly in the last decade of the study. Coexistence with HT might contribute to a better prognosis in cases of PTC.

Extrathyroidal extension predicts negative clinical outcomes in papillary thyroid cancer

BackgroundThe eighth edition American Joint Committee on Cancer tumor-node-metastasis staging for well-differentiated thyroid cancers, no longer considers “minimal” extrathyroidal extension for tumor staging. This change prompted us to examine the effect of extrathyroidal extension on patient outcomes. MethodsPatients (n = 177,497) in the 2016 National Cancer Database with classic papillary thyroid cancer were evaluated to determine the effect of extrathyroidal extension on overall survival and risk for nodal and distant metastases. Kaplan-Meier curves with the log-rank test were used to evaluate survival differences. Multivariable Cox and logistic regression analyses included relevant clinicopathologic variables (e.g. age, sex, race, and Charlson Comorbidity Index). ResultsPatients with “minimal” extrathyroidal extension had worse survival versus patients with no extrathyroidal extension (10-year survival 89.3% vs 93.1%, hazard ratio 1.23; 95% confidence interval, 1.13−1.35; P < .001). Any extrathyroidal extension was associated with higher risks for lymph node (odds ratio 2.78; 95% confidence interval, 2.69−2.87) and distant metastasis (odds ratio 3.5; 95% confidence interval, 3.05−4.04). These associations persisted when comparing “micro” (extension into the thyroid capsule) versus none for nodal risk (odds ratio 1.25; 95% confidence interval, 1.18−1.33) and distant metastasis (OR 1.52; 95% confidence interval, 1.11−2.09). ConclusionAll levels of extrathyroidal extension, including microscopic, were associated with increased risk for nodal and distant metastasis. Both minimal and macroscopic extrathyroidal extension were also associated with decreased overall survival. Such findings have the potential to affect the clinical decision making for patients diagnosed with papillary thyroid cancer.

Annexin A10 is a novel prognostic biomarker of papillary thyroid cancer.

The incidence of thyroid cancer (TC) is increasing rapidly worldwide. The target therapy for papillary TC (PTC) is limited, and the studies of PTC prognostic biomarkers are not common. As a new member of annexin A (ANXA) family, the function and clinical significance of ANXA10 in PTC have not been well investigated. Expressions of all the 12 ANXA members were detected with qPCR in 12 PTC tissues, and the ANXA10 mRNAs in PTCs and their adjacent normal thyroid tissues were compared. The subcellular location and expression of ANXA10 in 121 PTC patients were investigated with immunohistochemistry, which further classified the patients into subgroups with low or high ANXA10. The clinical significance and prognostic value of ANXA10 were estimated by analyzing its correlation with clinical factors and overall survival rates by the chi-squared test, univariate analyses, and multivariate analyses. ANXA10 had the highest expression in PTCs among all the ANXA members. Moreover, ANXA10 was significantly upregulated in PTC compared with normal thyroid tissues. The PTC patients with low and high expression of ANXA10 took up 70.25% (85/121) and 29.75% (36/121), respectively. ANXA10 expression was associated with tumor size, differentiation, and overall survival rates of PTC. ANXA10 was an independent prognostic biomarker predicting the poor outcome of PTC. ANXA10 expression was upregulated in PTC, and it was an independent prognostic biomarker of PTC, suggesting that ANXA10 may be a promising target for individual treatment of ANXA10.

Impact of Age-Related Genetic Differences on the Therapeutic Outcome of Papillary Thyroid Cancer.

The incidence of papillary thyroid carcinoma (PTC) has been increasing worldwide. PTC is the most common type of differentiated thyroid cancer and usually shows good prognosis. However, some PTC is driven to advanced stage by epithelial-mesenchymal transition (EMT)-mediated drug resistance, which is particularly noticeable in pediatric patients. There are limited options for systemic treatment, necessitating development of new clinical approaches. Here, we aimed to clarify genetic differences due to age of patients with PTC, and thereby aid in developing novel therapeutics. Patients with biochemically and histologically confirmed PTC were included in this study. PTC cells were acquired from young and older patients showing drug resistance, and were compared via microarray analysis. Cellular proliferation and other properties were determined after treatments with lenvatinib and sorafenib. In vivo, tumor volume and other properties were examined using a mouse xenograft model. Lenvatinib-treated group showed obvious suppression of markers of anti-apoptosis, EMT, and the FGFR signaling pathway, compared with control and Sorafenib-treated group. In the xenograft models, lenvatinib treatment induced significant tumor shrinkage and blocked the proto-oncogene Bcl-2 (B cell lymphoma/leukemia gene-2) and FGFR signaling pathway, along with reduced levels of EMT markers, compared with control and Sorafenib-treated group. Our findings clarify the age-dependent characteristics of pediatric PTC, giving insights into the relationship between young age and poor prognosis. Furthermore, it provides a basis for developing novel therapeutics tailored to the age at diagnosis.

Effect of prophylactic central neck dissection on the surgical outcomes in papillary thyroid cancer: experience in a single center

Morbidity due to papillary thyroid carcinoma (PTC) is increased mostly due to lymph node (LN) metastases, which lead to reoperations and complications associated with these operations. The aim is to compare the outcomes of PTC having total thyroidectomy and prophylactic central lymph node dissection (TT + PCND) with patients having total thyroidectomy (TT) alone. This study is a retrospective cohort analysis of 358 PTC patients that were operated by a single surgeon in a single center. Data about the patients were extracted from the medical records. Of the patient cohort, 258 patients had TT + PCND (42.5 ± 11.3years) and 100 patients (41.2 ± 11.9years) had only TT. Total number of LN extracted in the TT + PCND group was 8.1 ± 6.9. The mean number of metastatic LN were 2.2 ± 1.9. Percentage of patients that had RAI were less in the TT + PCND group compared to the TT group. Seven patients (2.7%) in the TT + PCND group and 19 (19.0%) in TT group had recurrent disease (p < 0.0001). Of the complications, only transient hypoparathyroidism was increased in TT + PCND group compared to TT group (26.7% vs 10%, p < 0.0001). TT + PCND performed by an experienced surgeon seems to decrease the number of LN recurrences, and the need for reoperations.

The Genetic Duet of BRAF V600E and TERT Promoter Mutations Robustly Predicts Loss of Radioiodine Avidity in Recurrent Papillary Thyroid Cancer.

BRAF V600E and TERT promoter mutations, particularly their genetic duet, are well known to be associated with poor clinical outcomes of papillary thyroid cancer (PTC). Loss of radioactive iodine (RAI) avidity in recurrent PTC is a major cause of treatment failure and hence poor clinical outcomes. This study investigated the role of mutation patterns in loss of RAI avidity in recurrent PTC. Methods: This was a retrospective study of the relationship between loss of RAI avidity in structural recurrent PTC and the genotype patterns of BRAF V600E and TERT promoter mutations in 164 patients (104 women and 60 men) with a median age of 50 y (interquartile range, 35-62 y). Results: The overall prevalence of RAI avidity loss in recurrent PTC was 62.8% (103/164). When the cohort was divided into mutation and wild-type groups, the RAI avidity loss was 80.4% versus 33.9% (P < 0.001) in BRAF V600E versus wild-type BRAF patients, with an adjusted odds ratio of 7.11 (95% confidence interval [CI], 3.24-16.27), and 89.4% versus 52.1% (P < 0.001) in TERT mutation versus wild-type patients, with an adjusted odds ratio of 6.89 (95% CI, 2.28-25.66). When the cohort was divided into 4 genotypes, the RAI avidity loss was 70.3% (45/64), 55.6% (5/9), and 97.4% (37/38) in patients with BRAF V600E alone, TERT mutation alone, and the genetic duet of coexisting BRAF and TERT mutations, versus 30.2% (16/53) in patients with neither mutation (P < 0.001, = 0.251, and < 0.001, respectively). These corresponded to odds ratios of 5.39 (95% CI, 2.31-13.13), 2.84 (95% CI, 0.53-16.32), and 81.04 (95% CI, 11.67-3559.83), respectively. The synergy index was 13.28 (95% CI, 1.54-114.46; P = 0.019) between BRAF V600E and TERT mutation in cooperatively affecting RAI avidity. A similar genotype-associated expression pattern was observed for thyroid iodide-handling genes. Conclusion:BRAF V600E alone and, particularly, coexisting BRAF V600E and TERT promoter mutations are strongly associated with loss of RAI avidity and impairment of the iodide-metabolizing machinery in recurrent PTC, showing a robust predictive value for failure of RAI treatment of PTC.

Programmed cell death 4 (PDCD4) as a novel prognostic marker for papillary thyroid carcinoma.

BackgroundThe primary goal of papillary thyroid cancer (PTC) management was to stratify patients at pre- and post-surgical level to identify the small proportion of cases with potentially aggressive disease.PurposeThe aim of our study is to evaluate the possible role of programmed cell death 4 (PDCD4) and BRAF status as prognostic markers in PTC.Patients and methodsWe investigate programmed cell death 4 (PDCD4) immunohistochemical expression in 125 consecutive PTCs with median follow-up of 75.3 months (range, 15–98 months) to verify the possible correlation between BRAF status and correlate the classical clinicopathological prognostic factors and PTC outcome with PDCD4 expression. To further support the data, miR-21 expression was tested (by quantitative real-time PCR and in situ hybridization) in a different series of 30 cases (15 PTCs BRAFwt and 15 PTCs BRAFV600E). Moreover, we validated our results using TGCA thyroid carcinoma dataset.ResultsWe found that 59.8% of the patients showed low-grade PDCD4 nuclear expression and low-grade expression correlated with BRAF V600E. Compared with BRAF 15 wild-type tissue samples, a significant miR-21 up-regulation was associated with BRAF V600E mutations. Low-grade PDCD4 resulted, and was associated with aggressive histological variants, higher cancer size, extra-thyroidal extension, multifocality, lymph-node metastasis and lymph nodal ratio at the diagnosis. Concerning the outcome, the low-grade PDCD4 expression correlated at univariate and multivariate analysis, with lower levels of recurrence-free survival rate (RFS) and with poor outcome. Moreover, there was significant association between BRAF V600E patients with PDCD4 nuclear loss and lower RFS, whilet here was significant association between BRAF wild-type patients with PDCD4 nuclear expression and better outcome.ConclusionThese results showed that PDCD4 could predict PTC outcome and that the sum of PDCD4 and BRAF alterations increases the prognostic power of BRAF mutation alone.