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Various studies have suggested that metabolic genes play a significant role in papillary thyroid cancer (PTC). The current study aimed to identify a metabolic signature related biomarker to predict the prognosis of patients with PTC. We conducted a comprehensive analysis on the data obtained from the Cancer Genome Atlas (TCGA) database. The correlation between survival result and metabolic genes was evaluated based on the univariate Cox analyses, least absolute shrinkage and selection operator (LASSO) and multivariate Cox analyses. The performance of a 7-gene signature was assessed according to Kaplan-Meier and receiver operating characteristic (ROC) analysis. Multivariate Cox regression analysis was adopted to unearth clinical factors related to the recurrence free survival (RFS) of patients with PTC. Finally, a prognostic nomogram was developed based on risk score, cancer status and cancer width to improve the prediction for RFS of PTC patients. Seven metabolic genes were used to establish the prognostic model. The ROC curve and C-index exhibited high value in training, testing and the whole TCGA datasets. The established nomogram, incorporating the 7-metabolic gene signature and clinical factors, was able to predict the RFS with high effectiveness. The 7-metabolic gene signature-based nomogram had a good performance to predict the RFS of patients with PTC. Our study identified a 7-metabolic gene signature and established a prognostic nomogram, which were useful in predicting the RFS of PTC.

Epigallocatechin-3-gallate is a natural polyphenolic compound that induces apoptosis in papillary thyroid cancer cells. However, its underlying molecular mechanism was not completely clarified. The present study demonstrated the role of apoptosis and autophagy in EGCG-treated papillary thyroid cancer cells and the relationship between these processes. EGCG significantly suppressed the viability of TPC-1 papillary thyroid cancer cells at an IC50 of 17.2 μM. EGCG induced TPC-1 cell apoptosis and cell cycle arrest at S phase and downregulated the protein expression of cyclin A and cyclin-dependent kinase-2. EGCG decreased reactive oxygen species levels, upregulated Bax expression, downregulated Bcl-2 expression and increased cytochrome C levels in the cytosol. Treatment with EGCG also increased the levels of cleaved caspase 3, cleaved caspase 9 and cleaved poly(ADP-ribose) polymerase. EGCG induced an autophagic response via the upregulation of the autophagy-related protein LC3-II and suppression of the AKT/mTOR signalling pathway. Autophagy inhibition further enhanced EGCG-induced cell apoptosis and ROS suppression, which indicated that autophagy played a cytoprotective role in EGCG-treated TPC-1 cells. Taken together, these results demonstrated that autophagy inhibition was beneficial to EGCG–mediated apoptosis in papillary thyroid cancer cells.

Background Thyroglobulin measurement in fine-needle aspiration (FNA-Tg) is an additional diagnostic tool of lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC). However, its performance as a preoperative indicator of lateral neck LNM in PTC is unclear. We evaluated the use of FNA cytology and FNA-Tg to detect neck LNM presurgery using a simple methodology, and established a cut-off value for diagnosing LNM in PTC. Methods We performed a retrospective cohort study based on hospital records, including 299 FNA-Tg measurements from 228 patients with PTC. The cut-off value for FNA-Tg was obtained through a receiver operating characteristic (ROC) curve analysis. The relationships between various parameters and FNA-Tg were analyzed using Spearman’s correlation. Results Of 299 lymph nodes (LNs) from 228 patients following surgery, 151 were malignant and 148 were benign. The median FNA-Tg levels were 414.40 ng/mL and 6.36 ng/mL in the metastatic and benign LNs, respectively. An FNA-Tg cut-off value of 28.3 ng/mL had the best diagnostic performance (93.38% sensitivity, 70.27% specificity, area under the ROC curve [AUC] 0.868) in the whole cohort. The diagnostic value performed better in the lateral neck group (level II–V, n = 163) than in the central neck group (level VI, n = 136); in the lateral neck group, the sensitivity and specificity of the FNA-Tg cut-off (16.8 ng/mL) were 96.25% and 96.36%, respectively. Conclusions FNA-Tg is a useful technique for the diagnosis of LNM before surgery, especially in lateral neck dissection. Clinical trial registration number ChiCTR1900028547.

Background Thyroid cancer is the most common malignant tumor of the endocrine system seen in the thyroid gland. More than 90% of thyroid cancers comprise papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Although anaplastic thyroid carcinoma (ATC) accounts for less than 2% of thyroid cancer. But patients' lifespan after diagnosis is about 6 months. Surgical interventions, radioactive iodine use, and chemotherapy are not sufficient in the treatment of ATC, so alternative therapies are needed. Methods and results The WST-1 assay test was performed to evaluate the anti-proliferative effects of Valproic acid (VPA). Also, the effect of VPA on miRNAs affecting histone deacetylase was determined by Quantitative RT-PCR. In the SW1736 cell line, IC50 dose for VPA was found 1.6 mg/ml. In our study, the level of oncogenic genes expression in cells treated with VPA, including miR-184, miR-222-5p, miR-124-3p, and miR-328-3p, decreased. Also, the expression of tumor inhibitory genes including miR-323-5p, miR-182-5p, miR-138-5p, miR-217, miR-15a-5p, miR-29b-3p, miR-324-5p and miR-101-5p increased significantly. Conclusions VPA can ad-just countless gene expression patterns, including microRNAs (miRNAs), by targeting histone deacetylase (HDAC). However, further studies are required for more accurate results.

Papillary thyroid cancer (PTC) is the predominant histological type of thyroid cancer, accounting for 80% of thyroid cancers. MiR-181a is a novel microRNA that is usually upregulated in multiple cancers. This study aims to explore the role and underlying mechanism of miR-181a in PTC. CCK8 and Transwell assays were performed to evaluate cell viability and migration. The mRNA level of miR-181a and KLF15 was calculated by qRT-PCR. The protein level of E-Cadherin, N-Cadherin and GAPDH was evaluated by western blot. Dual luciferase assay was conducted to validate that miR-181a directly targeting the 3′-UTR of KLF15 mRNA in TPC-1 cells. We observed that miR-181a was overexpressed and KLF15 was low expressed in PTC tissues and cell lines. Upregulation of miR-181a or downregulation of KLF15 predicted poor outcomes in PTC patients. MiR-181a improved cell growth of PTC, migration and epithelial–mesenchymal transition (EMT) in TPC-1 cells. KLF15 was a target gene of miR-181a and its expression was mediated by miR-181a. KLF15 partially reversed the facilitating effect of miR-181a on cell proliferation and migration in TPC-1 cells. We discovered that miR-181a served as an oncogene downregulating KLF15, thereby inhibiting cell proliferation, migration and the EMT. These findings demonstrate that miR-181a plays a significant role in PTC progression and could be a therapeutic target for PTC.

Background Endoscopic thyroidectomy is widely performed as it does not result in neck scar. However, there is a paucity of reports pertaining to completely endoscopic lateral neck dissection (LND). In this study, we introduce our step-wise approach for performing endoscopic selective LND via the chest–breast approach. We refer to this approach as Qin’s seven steps. Methods The Qin’s seven steps are: (1) establishment of working space range; (2) dissection of lymph nodes between the SCM and the sternohyoid muscle (level IV) and exposure of omohyoid; (3) dissection of lymph nodes at level IV; (4) dissection of lymph nodes at level III; (5) dissection of lymph nodes at carotid triangle (level III); (6) exposure of accessory nerve and dissection of lymph nodes at level II a; (7) dissection of lymph nodes at level II b. We reviewed the clinical data of 35 patients with papillary thyroid cancer (PTC) who were operated using the Qin’s seven steps. Results All 35 patients successfully underwent LND; bilateral LND was performed in 5 patients. The mean tumor size was 1.8 ± 1.0 cm; seven patients had multiple lesions. The mean number of retrieved lymph nodes in level II, III and IV were 8.8 ± 5.6, 6.1 ± 4.0 and 9.3 ± 5.1, respectively. As for complications, there were 3 cases of accessory nerve injury and 1 case of hypoglossal nerve injury. Internal jugular vein injury, cervical plexus injury and lymphatic leakage occurred in 2, 7, and 1 patients, respectively. Conclusion The Qin’s seven steps for performing endoscopic selective LND could be safely used in PTC patients with lateral lymph node metastasis. Satisfactory results were achieved in the short-term follow-up period. We recommend the use of Qin’s seven steps for PTC patients who are not desirous of neck scar.

Background Intra-tumor heterogeneity (ITH) results from the continuous accumulation of mutations during disease progression, thus impacting patients’ clinical outcome. How the ITH evolves across papillary thyroid carcinoma (PTC) different tumor stages is lacking. Methods We used the whole-exome sequencing data from The Cancer Genome Atlas Thyroid Cancer (TCGA-THCA) cohort to track the ITH and assessed its relationship with clinical features through different stages of the PTC progression. We further assayed the expression levels of the specific genes in papillary thyroid cancer cell lines compared to an immortalized normal thyroid epithelial cell line by qRT-PCR. Results We revealed the timing of mutational processes and the dynamics of the temporal acquisition of somatic events during the lifetime of the PTC. ITH significantly influences the PTC patient’s survival rate and, as genetic heterogeneity increases, the prognosis gets worse in advanced tumor stages. ITH also affects the mutational architecture of each clinical stage which is subject to periodic fluctuations. Different mutational processes may cooperate to shape a stage-specific mutational spectrum during the progression from early to advanced tumor stages. Moreover, different evolutionary paths characterize PTC progression across pathological stages due to both mutations recurrently occurring in all stages in hotspot positions and distinct codon changes dominating in different stages. A different expression level of specific genes also exists in different thyroid cancer cell lines. Conclusions Our findings suggest ITH as a potential unfavorable prognostic factor in PTC and highlight the dynamic changes in different clinical stages of PTC, providing some clues for the precision medicine and suggesting different diagnostic decisions depending on the clinical stages of patients. Finally, complete clear guidelines to define risk stratification of PTC patients are lacking; thus, this work could contribute to defining patients who need more aggressive treatments and, in turn, could reduce the social burden of this cancer.

Papillary thyroid cancer (PTC) is the most common subtype of thyroid cancer. The incidence of PTC is rising in tandem with an obesity epidemic. Associations have been demonstrated between increased body mass index (BMI) and worse oncological outcomes in a number of malignancies. However, research on this topic in PTC to date has been inconsistent, often due to limited data. This study aimed to measure the association between BMI and potentially adverse clinicopathological features of PTC. A meta-analysis of studies reporting outcomes after surgical treatment of PTC was performed. PubMed, Embase and the Cochrane Library were searched systematically to identify studies which provided data on BMI and clinicopathologic features of PTC. Relevant data were extracted and synthesis performed using adjusted odds ratios where available and crude values when not. Data were analysed by inverse variance using random and fixed effects models. Data on 35,237 patients from 15 studies met the criteria for inclusion. Obesity was associated with larger tumour size (MD = 0.17 cm [0.05, 0.29]), increased rates of multifocality (OR = 1.41 [1.16, 1.70]), extrathyroidal extension (OR = 1.70 [1.39, 2.07]) and nodal spread (OR = 1.18 [1.07, 1.30]). Associations were more pronounced as BMI increased. There was no association between BMI and bilaterality, vascular invasion or metastatic spread. Increased BMI is significantly associated with multiple potentially adverse features of PTC. The effect on long-term oncological outcomes requires further evaluation.

Papillary thyroid cancer (PTC) is commonly associated with neck lymph node metastasis (LNM), and recurrence does occur after radioactive iodine (RAI) ablation therapy. This study aimed to analyze the effectiveness of RAI ablation with regard to disease recurrence in intermediate-risk PTC patients with neck LNM. In addition, the study identified possible predisposing risk factors that might benefit from RAI ablation and analyzed common RAI therapy complications among these patients. A retrospective analysis of 349 intermediate-risk PTC patients with neck LNM who underwent thyroidectomy with neck dissection was performed. The oncologic results and clinicopathologic characteristics of these patients together with the incidence of postoperative RAI therapy complications were evaluated. Of the 349 patients, disease recurrence after treatment occurred for 27 patients (8%) during a mean follow-up period of 58.7 months (range 7–133 months). The recurrence-free survival curve of the patients who received postoperative RAI therapy (n = 208) did not differ significantly from that of the patients who did not receive it (n = 141) (P = 0.567). Nine patients without adjuvant RAI therapy (6%, 9/141) had recurrence. The recurrence rate for the central LNM patients without RAI therapy was only 2% (2/106). Both of these patients with recurrence had pathologic extranodal spread (ENS) and a high number (> 5) of metastatic central LNs. Postoperative RAI-related complications were observed in 24 patients (12%). Postoperative RAI is not necessary for intermediate-risk papillary thyroid cancer patients with central LNM, especially for patients with negative ENS and low number (< 5) of metastatic lymph nodes.

Circ_0137287 was found to be decreased in papillary thyroid cancer (PTC) tissues and related to aggressive clinicopathologic characteristics. However, the role and mechanism of circ_0137287 in PTC remain vague. Circ_0137287 expression was decreased in PTC and its low expression predicted poor survival. The ROC analysis suggested circ_0137287 might be a marker for PTC diagnosis. Circ_0137287 overexpression in PTC cells impaired cell proliferation, migration, invasion, and aerobic glycolysis, but induced apoptosis in vitro and in vivo. Circ_0137287 specifically bound to miR-183-5p, and miR-183-5p reversed the inhibitory effects of circ_0137287 on PTC tumor growth, motility and aerobic glycolysis. MiR-183-5p directly targeted PPP2R2A, and promoted PTC progression through regulating PPP2R2A. Mechanistically, circ_0137287 could indirectly modulate PPP2R2A expression through targeting miR-183-5p. Circ_0137287 suppressed PTC tumorigenesis and aerobic glycolysis through up-regulating PPP2R2A via miR-183-5p absorption, indicating a promising prognostic, diagnostic and therapeutic target.

Aim of this study was to evaluate the association between multiple essential microelements exposure and the aggressive clinicopathologic characteristics of papillary thyroid carcinoma (PTC). The concentrations of 10 essential microelements in urine [cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), molybdenum (Mo), selenium (Se), strontium (Sr), zinc (Zn), and iodine (I)] were measured in 608 patients newly diagnosed with PTC, including 154 males and 454 females. Chi square test and Wilcoxon rank sum test were used to compare general characteristics among males and females. Multivariate logistic regression was used to evaluate the associations between essential microelements and PTC clinicopathologic characteristics in single- and multi-microelement models. In this study, we only observed that the frequency of lymph node metastasis in males was higher than in females, and males had higher levels of zinc than females, but males had lower levels of iodine than females. It was found that high levels of Fe were associated with decreased risk of PTC tumor size > 1 cm, capsular invasion, and advanced T stage (T3/4a/4b). High levels of Co and Mo were associated with decreased risk of capsular invasion and lymph node metastasis, respectively. However, high levels of Mn and Sr were associated with increased risk of capsular invasion and multifocality respectively, and both were associated with increased risk of advanced T stage (T3/4a/4b). These findings indicated that certain essential microelements might have potential effects on PTC progression and aggressiveness. Further studies are required to confirm these findings.

The 2015 American Thyroid Association guidelines endorsed lobectomy for patients with low-risk papillary thyroid cancer (PTC) measuring 1–4 cm. Attitudes about the use of lobectomy for these patients are lacking, particularly from low-volume surgeons who perform the majority of thyroidectomies in the US. A survey was mailed to 1000 surgeons stratified by specialty (500 general surgeons and 500 otolaryngologists) registered with the American Medical Association, to evaluate beliefs and practices about the extent of surgery for low-risk PTC. Comparisons examined differences by surgeon volume. Of 320 respondents who have performed thyroidectomy since 2015 (150 general surgeons, 170 otolaryngologists), 206 (64.4%) were low volume ( 1 cm. Awareness of guidelines and concerns about increased risk of recurrence after lobectomy may drive surgeons’ preference for total thyroidectomy.

Up to 40% of papillary thyroid cancer (PTC) patients have lymph node metastasis, a condition that implies persistent, recurrent, or progressive disease. However, the American Joint Committee on Cancer Manual states that there is no reliable examination for adequate lymph node staging. Therefore, our aim is to develop a lymphatic imaging technique using ultrasonography to address this challenge. We consecutively enrolled PTC patients who underwent ultrasound (US) lymphatic imaging via the peritumoral injection of contrast media. Identification of the sentinel lymph nodes and the targeted sentinel lymph nodes was separately based on the lymphatic drainage pathway and the enhancement patterns. Every identified targeted node was assigned a score, according to the features on conventional US and enhancement patterns, and was referred for ultrasound-guided fine-needle aspiration. Cytological and histopathologic results represented the statuses of the targeted lymph nodes and overall central lymph nodes, respectively, which were applied to evaluate the diagnostic performance of US lymphatic imaging. In total, 100 PTC patients were included. On the basis of the cytological results, the sensitivity (97.1%, 95% confidence interval [CI]: 84.7–99.9%) of detecting positive targeted nodes by US lymphatic imaging significantly increased by 45.5% at a threshold of 4 or higher (p = 0.0001), without loss of specificity (p = 1.0000). The surgical results showed that the metastatic degree was positively correlated with an increase in the score (τ: 0.671, p < 0.001). Ultrasound lymphatic imaging has a high diagnostic performance, and its corresponding scoring system facilitates grading of the nodal burden in the central compartment. • Ultrasound neck lymphatic imaging is an effective contrast-enhanced ultrasound (CEUS) technique (applied after the peritumoral injection of contrast media) for identifying sentinel lymph nodes in the central compartment by tracing the imaged afferent lymphatic vessel. • Lack of enhancement or perfusion defects is the typical enhancement pattern for recognizing the involved central lymph nodes. • Ultrasound lymphatic imaging for identification of positive central lymph nodes before surgery may effectively avoid complications associated with the surgical sentinel node procedure.

Longer time to surgery worsens survival in multiple malignancies, including lung, colorectal, and breast cancers, but limited data exist for well-differentiated thyroid cancer. We sought to investigate the impact of time to surgery on overall survival in patients with papillary thyroid cancer. In a retrospective cohort study of the National Cancer Database, we used Cox proportional hazard models to investigate overall survival as a function of time between diagnosis and surgery for adults with papillary thyroid cancer, adjusting for demographic, patient, and cancer-related variables. Time to surgery was investigated both as a continuous variable and as intervals of 0–90 days, 90–180 days, and > 180 days. Subgroup analyses were conducted by T stage. Overall, 103,812 adults with papillary thyroid cancer were included from 2004 to 2016. Median follow-up was 55.2 months (interquartile range 28.4–89.5). Increasing time to surgery was associated with increased mortality: delaying by 91–180 days increased the risk by 30% (adjusted hazard ratio [aHR] 1.30, 95% CI 1.19–1.43) and delaying by over 180 days increased the risk by 94% (aHR 1.94, 95% CI 1.68–2.24). Five-year overall survival was 95.7% for 0–90 days, 93.0% for 91–180 days, and 87.9% for over 180 days. On subgroup analysis, increasing delay was associated with worse overall survival for T1, T2, and T3 tumors, but not T4 tumors. Increasing time to surgery in papillary thyroid cancer is associated with reduced overall survival. Further research is necessary to assess the impact of surgical delay on disease-specific survival.

Adiponectin (Acrp30) and leptin, adipokines produced and secreted mainly by the adipose tissue, are involved in human carcinogenesis. Thyroid carcinomas are frequent endocrine cancers, and several evidences suggest that they are correlated with obesity. In this study, we first analyzed the expression levels and prognostic values of Acrp30, leptin, and their receptors in thyroid cancer cells. Then, we investigated the role of Acrp30 and leptin in proliferation, migration, and invasion. We found that Acrp30 treatment alone inhibits cell proliferation and cell viability in a time and dose-dependent manner; leptin alone does not influence thyroid cancer cells (BCPAP and K1) proliferation, but the combined treatment reverts Acrp30-induced effects on cell proliferation. Additionally, through wound healing and Matrigel Matrix invasion assays, we unveiled that Acrp30 inhibits thyroid cancer cell motility, while leptin induces the opposite effect. Importantly, in the combined treatment, Acrp30 and leptin exert antagonizing effects on papillary thyroid cancer cells’ migration and invasion in both BCPAP and K1 cell lines. Highlights of these studies suggest that Acrp30 and leptin could represent therapeutic targets and biomarkers for the management of thyroid cancer. Supplementary Information The online version contains supplementary material available at 10.1007/s13105-021-00789-x.

Understanding the method of thyroid cancer detection has potential implications on interpreting incidence rates, the diagnosis and management of thyroid cancer. We conducted a systematic review of studies reporting methods of thyroid cancer detection to estimate the frequency of incidentally found cancers and classify triggers of incidental thyroid cancer diagnosis. We searched multiple bibliographic databases from inception to June 2020. A pair of reviewers, working independently and in duplicate selected studies for inclusion, extracted data, and evaluated each trial’s risk of bias. Studies enrolling patients older than 18 years with thyroid cancer confirmed histologically were included. In total, 17 cohorts and 1 cross-sectional study, conducted between 1991 and 2018, enrolling 4668 patients with thyroid cancer were included: 88% had papillary thyroid cancer and 23% had papillary thyroid microcarcinoma. The proportion of patients with non-incidental and incidental thyroid cancer was similar: 49% [95% confidence interval (CI): 40–58%]. Subgroup analysis showed that most patients with incidental thyroid cancers had tumor size 45 (61%; 95% CI: 56–67%), and were detected through imaging (35%; 95% CI: 26–45%), of which ultrasound was the most common modality (27%; 95% CI: 14–43%). The heterogeneity for all the effect sizes was large and significant. About half of thyroid cancers were found incidentally through the use of imaging studies, in particular neck ultrasound. These incidentally found cancers were mostly small papillary thyroid cancer. These results highlight opportunities for interventions aimed at reducing drivers of overdiagnosis.

In the thyroid gland, radiofrequency ablation (RFA) is being applied to both benign nodules and cancers internationally, while interest is also growing in the West. Benign thyroid nodules (BTNs) may be candidates for intervention when symptoms develop. For differentiated thyroid cancers (DTC), surgery is currently the first-line treatment. However, for candidates with high surgical risk or those who refuse to undergo repeated surgery, newer techniques such as RFA are an option. Surgery is associated with complications including hypothyroidism, voice change, hypocalcemia, and a scar. RFA has been used in Asian and European institutions as an alternative to surgery, but is relatively new in North America. Although RFA is not associated with significant complications, few randomized control trials have assessed its efficacy. The studies to date suggest a low rate of severe complications and a small need for thyroid hormone replacement following RFA. Further large-scale studies focusing on a Western population are needed. The aim of this review is to evaluate the evidence with respect to the current studies and data about the safety and efficacy of radiofrequency ablation for the management of BTNs and DTC. We systematically searched the PubMed/MEDLINE, EMBASE, Clinical Queries, and Web of Science databases, for articles published up to April 30th, 2020. Total of 75 studies that met the inclusion criteria were included in the review. Thirty-five studies focused on RFA use for solid nodules, 12 studies on predominantly cystic nodules, 10 for autonomously functioning thyroid nodules, and 18 studied were published on differentiated thyroid cancer. RFA seems to be an effective and safe alternative to surgery in high-risk surgical patients with thyroid cancers and for selected BTNs. Additional trials with longer follow-up in North American patients are needed to validate its full role in the armamentarium of thyroid ologists.

To evaluate the diagnostic accuracy of preoperative contrast-enhanced ultrasound (CEUS) to detect extracapsular extension (ECE) and identify the relationship between ECE and nodule enhancement patterns in patients with papillary thyroid cancer (PTC). Patients with suspected thyroid cancer underwent ultrasound (US) and CEUS examinations. The US and CEUS features of the PTC nodules and thyroid capsule were recorded and classified individually. The accuracy of US and CEUS in detecting ECE was compared individually, and its relationship with various tumour enhancement patterns was analysed. The presence or absence of ECE and cervical lymph node metastasis (LNM) was confirmed pathologically. The final dataset included 119 patients with 124 PTC nodules. Seventy-two (60.5%) of these patients with PTC had no ECE (including 38 patients with single capsule invasion), while the remaining 52 had ECE. A significant difference was found in nodules with non-capsule invasion, single capsule invasion, and ECE between the cervical LNM and non-LNM groups (p < 0.01). Receiver operating characteristic curve analysis demonstrated that area under the curve (AUC) of ECE for cervical LNM was higher than that of capsule invasion (71.9% vs. 49.6%). Moreover, the CEUS images acquired to detect ECE showed higher AUC values than those of US images (79.4% vs. 65.8%) (p = 0.02). Among the PTC nodules with differential enhancement, hyper-enhanced nodules had the highest incidence of capsule invasion (41.9%), while hypo-enhanced ones had a higher incidence of ECE (47.4%). Compared with conventional US, CEUS is a more valuable and non-invasive imaging modality to detect ECE. • Single capsular invasion was a poor predictor of cervical lymph node metastasis, while extracapsular extension assessments were clinically significant for predicting cervical lymph node metastasis. • CEUS is better than conventional US in detecting extracapsular extension in papillary thyroid carcinoma (AUC: 79.4% vs. 65.8%) (p = 0.02). • Among the thyroid papillary carcinoma nodules with differential enhancement, hyper-enhanced nodules had the highest incidence of single capsule invasion (41.9%), while hypo-enhanced ones had a higher incidence of ECE (47.4%).

The incidence of papillary thyroid cancer (PTC), the major type of thyroid cancer, is increasing rapidly around the world, and its pathogenesis is still unclear. There is poor prognosis for PTC involved in rapidly progressive tumors and resistance to radioiodine therapy. Kinase gene fusions have been discovered to be present in a wide variety of malignant tumors, and an increasing number of novel types have been detected in PTC, especially progressive tumors. As a tumor-driving event, kinase fusions are constitutively activated or overexpress their kinase function, conferring oncogenic potential, and their frequency is second only to BRAFV600E mutation in PTC. Diverse forms of kinase fusions have been observed and are associated with specific pathological features of PTC (usually at an advanced stage), and clinical trials of therapeutic strategies targeting kinase gene fusions are feasible for radioiodine-resistant PTC. This review summarizes the roles of kinase gene fusions in PTC and the value of clinical therapy of targeting fusions in progressive or refractory PTC, and discusses the future perspectives and challenges related to kinase gene fusions in PTC patients.

ObjectiveTo assess the capacity of support vector machine (SVM) algorithms that are developed based on platelet RNA-seq data in identifying thyroid neoplasm patients and differentiating patients with thyroid adenomas, papillary thyroid cancer and metastasized papillary thyroid cancer.MethodsPlatelets were collected and isolated from 109 patients and 63 healthy controls. RNA-seq was performed to find transcripts with differential levels. Genes corresponding to these altered transcripts were identified using R packages. All samples were subsampled into a training set and a validation set. Two SVM algorithms were developed and trained with the training set, using the genes with differential transcript levels (GDTLs) as classifiers, and validated with the validation set. GO and KEGG pathway enrichment analysis were performed using the R package clusterProfiler.ResultsWe detected 765 GDTLs (442 up-regulated and 323 down-regulated) in platelets of patients and healthy controls. The algorithm identifying thyroid neoplasm patients achieved an accuracy of 97%, with an AUC (area under curve) of 0.998. The other algorithm differentiating patients with multiclass thyroid neoplasms had an average accuracy of 80.5%. GO analysis showed that GDTLs were strongly involved in biological processes such as neutrophil degranulation, neutrophil activation, autophagy and regulation of multi-organism process. KEGG pathway enrichment analysis revealed that GDTLs were mainly enriched in NOD-like receptor signaling pathway and pathways in endocytosis, osteoclast differentiation, human cytomegalovirus infection and tuberculosis.ConclusionOur results indicated that the combination of SVM algorithms and platelet RNA-seq data allowed for thyroid neoplasm diagnostics and multiclass thyroid neoplasm classification.

PURPOSE: Xeroderma pigmentosum (XP) is an autosomal recessive disease with defective DNA repair, a markedly increased risk of skin cancer, and premature aging. Reports from North Africa have described thyroid nodules in XP patients, but thyroid nodule prevalence has never been determined in XP patients enrolled in our natural history study at the National Institutes of Health (NIH). METHODS: We performed thyroid ultrasound examinations on all 29 XP patients examined from 2011 to 2019 and assessed nodule malignancy using the Thyroid Imaging Reporting and Data System. Thyroid nodule prevalence was also obtained from comparison cohorts. DNA sequencing was performed on thyroid tissue from XP patients who had surgery for thyroid cancer. RESULTS: Thyroid nodules were identified in 18/29 XP patients (62%). The median age of patients with thyroid nodules in our XP cohort (20 years) was younger than that of three comparison groups: 36 years (California study - 208 subjects), 48 years (Korean study – 24,757 subjects), and 52 years (NIH – 682 research subjects). Multiple (2 to 4) thyroid nodules were found in 12/18 (67%) of the patients with nodules. Autopsy examination revealed follicular adenomas in 4/8 (50%) additional XP patients. DNA sequencing revealed rare mutations in two other XP patients with papillary thyroid cancer. CONCLUSIONS: XP patients have an increased incidence of thyroid nodules at an early age in comparison to the general population. These finding confirm another premature aging feature of XP.

Pralsetinib (GAVRETO™, Blueprint Medicines Corporation) is a selective rearranged during transfection (RET) inhibitor being developed for the treatment of various solid tumours. RET is a well described proto-oncogene present in multiple cancers including non-small cell lung cancer (NSCLC), papillary thyroid cancer, and medullary thyroid carcinoma (MTC). Pralsetinib was recently granted accelerated approval for the treatment of metastatic RET fusion-positive NSCLC in the USA and is under regulatory review in the USA for RET fusion-positive thyroid cancer and RET mutation-positive MTC; pralsetinib is under regulatory review in the EU for RET fusion-positive NSCLC. This article summarizes the milestones in the development of pralsetinib leading to this first approval.

Investigating novel biomarkers discriminating thyroid nodules is a matter of great importance for differential diagnosis. The current study was planned to investigate the diagnostic value of fibulin-1 in plasma specimens of patients with thyroid nodules. A literature review was also performed to gain an understanding of the existing research relevant to the main role of fibulin-1 in carcinogenesis. In this case-control study, the levels of plasma fibulin-1 were compared in 82 subjects including papillary thyroid cancer (PTC; n = 30), multinodular goiter (MNG; n = 30), and healthy subjects (n = 22) using enzyme-linked immunosorbent assay (ELISA). Fibulin-1 levels of patients with PTC and MNG were documented to be significantly lower than those of healthy subjects (PTC vs. Healthy; P = 0.000, MNG vs. Healthy; P = 0.000). No statistically significant differences were found between PTC and MNG groups when fibulin-1 levels were compared (P > 0.05). Low level of plasma fibulin-1 was associated with an increased risk of PTC tumorigenesis (odds ratio = 0.810; 95% CI: 0.704–0.933; P = 0.003). Further, fibulin-1 had an appropriate diagnostic value for detecting PTC patients with a sensitivity of 73.33%, and specificity of 100% at the cutoff value > 4.9 (ng/ml). According to the results of the present research which are tied well with previous studies, the abnormal downregulation of fibulin-1 may play a role in the PTC and MNG tumorigenesis. In addition, fibulin-1 probably promotes the development and progression of other human cancer; however, further studies are needed to improve current understandings.

Anaplastic thyroid cancer (ATC) is a rare, aggressive form of undifferentiated thyroid cancer, which exhibits rapid progression and is almost universally fatal. At least a subset of ATC is thought to arise from pre-existing well-differentiated thyroid cancer, most frequently papillary thyroid cancer (PTC). While PIK3CA mutations are rare in PTC, they are common in ATC and tend to co-occur with BRAF mutations. This provided the rationale for our study to identify the potential role of PIK3CA mutations in the progression from well-differentiated to undifferentiated thyroid cancer. We introduced PIK3CAE545K into the LAM1 PTC cell line, which carries a BRAFV600E mutation. In culture, the engineered cell line (LAM1:PIK3CAE545K) proliferated faster and demonstrated increased clonogenic potential relative to the parental line carrying an empty vector (LAM1EV). Both the LAM1EV and LAM1:PIK3CAE545K edited lines were implanted into hind flanks of athymic nude mice for in vivo determination of disease progression. While tumour weights and volumes were not significantly higher in LAM1:PIK3CAE545K mice, there was a decrease in expression of thyroid differentiation markers TTF-1, thyroglobulin, PAX8 and B-catenin, suggesting that introduction of PIK3CAE545K led to dedifferentiation in vivo. Collectively, this study provides evidence of a role for PIK3CAE545K in driving disease progression from a well-differentiated to an undifferentiated thyroid cancer; however, over-expression was not a determinant of an accelerated growth phenotype in ATC. Graphical Abstract

Background Melanoma develops in the cells that produce melanin; ocular melanoma accounts for 3–4% of all malignant melanomas. Thyroid tumors are the most common endocrine neoplasms, with more than 95% of cases arising from follicular cell origin. Previous studies have reported associations between malignant melanoma and a wide variety of malignancies. Case presentation We report a 54-year-old Iranian woman who was diagnosed with ocular melanoma based on a mushroom-shaped filling defect with homogeneous echo pattern arising from the anterior third of the temporal side of the globe detected on ocular sonography during routine ophthalmological examination. She underwent right globe enucleation and implant replacement. During tumor surveillance, fluorodeoxyglucose positron emission tomography/computed tomography scan showed low-grade metabolically active tumoral involvement in the anterolateral aspect of the right lobe of thyroid. The patient subsequently underwent thyroidectomy and submandibular lymphadenectomy. Pathologic report demonstrated micropapillary carcinoma (9 × 8 mm2), tall cell variant without lymphovascular or perineural invasion in the base of lymphocytic thyroiditis. Conclusion This case illustrates the importance of precise active surveillance in case of papillary carcinoma of thyroid or malignant melanoma to avoid missing other associated pathologies and emphasizes the simultaneous treatment of two tumors.

Papillary thyroid microcarcinoma (mPTC) is defined as a papillary thyroid cancer sized 10 mm or less. Despite their generally indolent clinical course and good prognosis, a subset of mPTCs shows potentially aggressive behaviour. To search for predictors of clinical outcome of mPTCs, we retrospectively evaluated the genetic tumour profile of 100 patients (23 M/77 F, mean age ± SD 53.8 ± 13.4 years) with histologically confirmed mPTCs through analysis of BRAF, NRAS and TERT promoter mutations as well as RET/PTC translocations. Mean follow-up period was 8.4 ± 3.6 years. In 55 cases, mPTC were detected incidentally after surgery. Capsular invasion, bilateralism and multifocality were found in 11/100, 17/100 and 24/100 cases, respectively, while lymph-nodes metastases were present at diagnosis in 9/100 cases. After 3.5 ± 2.0 years, tumour relapse occurred in 6/100 cases and was locoregional in five (two in the thyroid bed, three in laterocervical lymph-nodes), while lung metastasis occurred in one case. Biochemical persistence of disease was seen in 1/100 case. Mutations occurred in 55/100 cases; BRAFV600E was the most frequently detected (49/100) and was associated with higher tumour size, bilateralism and follicular variant but not with capsular invasion. RET/PTC rearrangements were found in 2/100 cases, NRASQ61R in 4/100, while no mutations of TERT promoter gene were detected. Despite the observed association between BRAFV600E mutation and unfavourable histopathological features, we found no direct association with tumour recurrence, distant metastases and mortality. In our study, the search for the most frequent genetic alterations as prognostic markers in mPTCs would not have changed the therapeutic strategy.

While papillary thyroid cancer (PTC) has largely favorable prognosis, anaplastic thyroid cancer (ATC) is a rare but extremely aggressive malignancy with grim clinical outcome. Even though new therapeutic options are emerging for ATC, additional preclinical models and novel combinations are needed for specific subsets of patients. We established a novel cell line (PF49) from the malignant pleural effusion of a 68-year-old male patient with ATC that rapidly transformed from a BRAF and TERT promoter mutant PTC. PF49 cells demonstrated a robust migratory activity in vitro and strong invasive capacity in vivo in a pleural carcinosis model. Combined BRAF and MEK inhibition decreased the proliferation and migration of PF49 cells, however could not induce cell death. Importantly, HDAC inhibitor treatment with SAHA or valproic acid induced cell cycle arrest and strongly increased PD-L1 expression of the tumor cells. Induction of PD-L1 expression was also present when paclitaxel-cisplatin chemotherapeutic treatment was combined with HDAC inhibitor treatment. Increased PD-L1 expression after HDAC inhibition was recapitulated in an international ATC cell model. Our data suggest that HDAC inhibition alone or in combination with standard chemotherapy may potentiate anaplastic thyroid cancer cells for immunotherapy. Electronic supplementary material The online version of this article (10.1007/s12253-020-00834-y) contains supplementary material, which is available to authorized users.

To investigate the value of radiomics analysis of dual-energy computed tomography (DECT)–derived iodine maps for preoperative diagnosing cervical lymph nodes (LNs) metastasis in patients with papillary thyroid cancer (PTC). Two hundred and fifty-five LNs (143 non-metastatic and 112 metastatic) were enrolled and allocated to training and validation sets (7:3 ratio). Radiomics features were extracted from arterial and venous phase iodine maps, respectively. Radiomics signature was constructed based on reproducible features using the least absolute shrinkage and selection operator (LASSO) logistic regression algorithm with 10-fold cross-validation. Logistic regression modeling was employed to build models based on CT image features (model 1), radiomics signature (model 2), and the combined (model 3). A nomogram was plotted for the combined model and decision curve analysis was applied for clinical use. Diagnostic performance was assessed and compared. Internal validation was performed on an independent set containing 78 LNs. Model 3 showed optimal diagnostic performance in both training (AUC = 0.933) and validation set (AUC = 0.895), followed by model 2 (training set, AUC = 0.910; validation set, AUC = 0.847). Both these two models outperformed model 1 in both training (AUC = 0.763) (p

INTRODUCTION: Aggressive variants of papillary thyroid cancer (PTC) have been described with increasing frequency. These variants include diffuse sclerosing variant, tall cell variant, columnar cell variant, solid variant, and hobnail variant. METHODS: We have performed a review of the more aggressive variants of PTC with respect to main characteristics, histological and molecular features, and the consequences that the knowledge of these variants should have in the treatment of the patients. RESULTS: At the present time, we do not know the prognostic value of these aggressive PTC variants. The extent of the surgical treatment and adjuvant therapy necessary should be decided on the basis of the extent of the tumor at presentation and the opinion of experienced clinicians. CONCLUSION: These aggressive variants should be known by clinicians, to avoid underdiagnosis, and treated according to the latest recommendations in the literature. ispartof: ADVANCES IN THERAPY vol:37 issue:7 pages:3112-3128 ispartof: location:United States status: published

The aim of this study was to evaluate the clinicopathologic characteristics and pattern of lymph node (LN) metastasis in papillary thyroid cancer (PTC) located in the isthmus. A systematic review of the relevant electronic databases was conducted between January 2000 and December 2019, including Pubmed, Web of Science, and the China Journal Net. Outcomes of interest included gender, age, tumor size, multifocality, capsule invasion, extrathyroidal extension, and lymph node metastasis. We calculated the pooled odds ratios (ORs) with 95% confidence intervals (CIs) for each study using a random or fixed effect model. Nine studies with a total of 4541 patients were included. Patients with isthmic PTC were 565 (12.4%). Our meta-analysis revealed that there was a significant association between the isthmus location and multifocality (OR = 1.50; 95% CI = 1.18–1.90), capsule invasion (OR = 1.53; 95% CI = 1.17–1.99), extrathyroidal extension (ETE) (OR = 1.95; 95% CI = 1.34–2.86), and central LN metastasis (OR = 1.53; 95% CI = 1.17–1.99). For patients with solitary nodule, our meta-analysis illustrated that there was a significant association between the isthmus location and ETE (OR = 1.65; 95% CI = 1.11–2.46), and central LN metastasis (OR = 2.50; 95% CI = 1.82–3.44). However, the meta-analysis suggested that there was no correlation between the isthmus location and lateral LN involvement (OR = 1.04; 95% CI = 0.58–1.87). PTCs located in the isthmus were associated with multifocality, capsule invasion, ETE, and more likely to involve the central lymph node.

Background: The familial nonmedullary thyroid cancer (FNMTC) is suspected to be a Mendelian condition in up to 3–8% of thyroid cancers. The susceptibility chromosomal loci and genes of 95% of FNMTC cases remain to be characterized. The inheritance of FNMTC appears to be autosomal dominant with incomplete penetrance and variable expressivity. The finding of the causative gene of FNMTC and the identification of patients at risk that need genetic testing were our aim. Methods: We analyzed by whole-exome sequencing patients and non-affected relatives of five families with at least two family members affected by papillary thyroid cancer, selecting for new or extremely rare variants with predicted pathogenic value. Results: A family showed, in all three affected members, a new loss-of-function variant (frameshift deletion) in BROX gene at 1q41 that was absent from all internal and external databases. In a second family with three affected relatives, we found an additional new BROX variant. The smaller families presented no variants in BROX or in the other causative genes studied. Conclusions: BROX could be a new causative gene for FNMTC. Variants in BROX may result in the haploinsufficiency of a key gene involved in the morphogenesis of MVBs, in the endosomal sorting of cargo proteins, and in EGFR. Functional studies are needed to support this result. The thorough genomic analysis by NGS in all families with three or more affected members should become a routine approach to obtain a comprehensive genetic view and find confirmative second cases.

We aimed to investigate inflammation indices based on preablation hematological parameter of the lymphocyte-to-monocyte ratio (LMR) to predict the clinical outcome in papillary thyroid cancer (PTC) patients with low- and intermediate-risk stratification. This retrospective study analyzed 772 patients with low- and intermediate-risk PTC who underwent total thyroidectomy followed by radioiodine therapy between July 2005 and July 2009 with a median of 10 years. Kaplan–Meier statistics were used to test differences in recurrence-free survival (RFS) between groups based on the optimal cutoff point of biomarkers identified using receiver operating characteristic curves. With an optimal cutoff point of 7.05, 215 patients (29.8%) were classified as having low LMR and 557 patients (71.2%) were classified as having high LMR. High LMR was significantly associated with a prolonged RFS (hazard ratio [HR]: 2.048, 95% confidence interval [CI]: 1.062–4.359, p = 0.001). Multivariate analysis showed that low LMR (HR = 2.035, 95% CI: 1.011–4.095, p = 0.012), tumor size over 2 cm (HR = 2.762, 95% CI: 1.303–5.852, p = 0.008), and high preablative simulated thyroglobulin level over 10 ng/ml (HR = 7.826, 95% CI: 2.353–26.033, p

To describe the outcomes and the incidence of adverse events following active surveillance (AS) versus immediate surgery in patients with low-risk papillary thyroid carcinoma (PTC). We prospectively evaluated 286 patients who attended the Hospital de Clinicas, with a single thyroid nodule

In the current era of de-escalation of surgical treatment for low-risk thyroid cancer, it is important to ensure that the natural history of thyroid cancer is as benign as has been suggested previously. We therefore compared the impact of surgery refusal and surgery on disease-specific survival (DSS) in patients with local or regional, papillary thyroid cancer (PTC). Local and regional stage PTC patients in the Surveillance, Epidemiology, and End Results Program (1988–2015) were included. Cox proportional hazard modeling and propensity score matching were conducted to evaluate DSS. There were 45,136 patients who received surgery and 146 patients who had surgery recommended but refused. Adjusted analysis showed a significantly better DSS for the surgery group compared with the refusal group (HRadj: 3.07 (95% CI: 1.54–6.11). After stratification for stage, no statistically significant difference in DSS was found (HRadj: 3.03 (0.89–10.35) when including only local stage PTC. Propensity matching showed a 10-year DSS of 94.0% (95% CI: 87.7–97.1%) and 96.4% (95% CI: 93.2–98.1%) for the refusal and surgery group (p = 0.060). Propensity matching of local stage PTC showed a 10-year DSS of 96.7% (95% CI: 89.9–98.9%) and 100%, respectively (p = 0.002). Although no significant difference in survival was found between surgery and no surgery in local stage PTC, a 3.3% improvement of 10-year DSS was found in the surgery group. Overall, these results suggest that local stage PTC has a benign natural history, and that conservative management strategies such as active surveillance may be appropriate.

This retrospective study investigated the association between worrisome pathological features of papillary thyroid cancer indicative of invasion and type 2 diabetes, as well as antihyperglycemic drug therapy for diabetes. The records of 14,167 patients who had undergone primary surgery for thyroid cancer were retrospectively reviewed and screened for concomitant diabetes. The diabetic and nondiabetic groups were age and gender matched, and further stratified by treatment, including five single antihyperglycemic drugs. The study population comprised 942 patients, including 471 patients each with and without diabetes. The rate of worrisome pathological features was higher in diabetic patients than in nondiabetic patients (49.26% cf. 30.57%, P

To explore the association between the thyroid stimulating hormone receptor (TSHR) gene methylation and human papillary thyroid cancer (PTC), as well as PTC related clinicopathological indicators. We searched PubMed, Embase, Medline, and Web of Science databases through computer for articles published in English on association between methylation of TSHR gene and PTC. Articles published in Chinese were searched in China National Knowledge Infrastructure (CNKI), WanFang, China Biology Medicine (CBM) disc, and WeiPu databases. Database search took place in the 4th week of October. Totally 914 samples from 14 case-control studies were included in our meta-analysis. The methylation rate of TSHR gene in PTC group was significantly greater than that in control group (OR = 6.45, 95% CI 3.03, 13.71, P 0.1). The rate of TSHR gene methylation is higher in PTC and it may be associated with the pathogenesis of human PTC, suggesting that TSHR gene may be a candidate marker for PTC diagnosis. In addition, the occurrence of TSHR gene methylation in PTC patients is closely related to age, lymph node metastasis, clinical stage, and tumor size, suggesting that TSHR gene may be used as an index to judge the severity of PTC.

In 2016, Nikiforov et al. (JAMA Oncol 2:1023-1029, 2016) proposed replacing the term "non-invasive encapsulated follicular variant of papillary thyroid carcinoma" (FVPTC) with the term "non-invasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP). In 2018, to avoid the misdiagnosis of papillary thyroid cancer as NIFTP, the authors proposed changes to the criteria for NIFTP classification. Some previous studies evaluated the impact of NIFTP on the risk of malignancy (ROM) in the fine-needle aspiration cytology (FNAC) diagnostic categories according to the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). However, little is known about the influence of an NIFTP diagnosis on ROM on the basis of the revised criteria. The aim of this study was to assess the influence of NIFTP on ROM using the revised diagnostic criteria. The present study included 998 thyroid nodules that were diagnosed and resected at the same medical center. All specimens with a diagnosis of cancer were reviewed to identify NIFTP according to the revised 2018 criteria. Additionally, molecular diagnostics were performed to detect the BRAF p.V600E mutation and TERT promoter mutations in all the NIFTP cases. The number of cases that met the revised criteria was determined, and the ROM was calculated in each of the FNAC diagnostic categories. Only five cases (2.3% of all papillary thyroid carcinoma diagnoses) were considered NIFTP, according to the 2018 criteria. With respect to the FNAC category, one case was a follicular neoplasm or suspicious for a follicular neoplasm (FN/SFN), three cases were suspicious for malignancy (SM), and one case was malignant (M). The ROM decreased in each of the Bethesda categories (0.7% in FN/SFN, 4.3% in SM, and 0.5% in M) when a diagnosis of NIFTP was taken into account. These reductions were not statistically significant. These data indicate that the NIFTP entity has very little impact on ROM for the diagnostic categories of the Bethesda system.

Ultrasonography (US) is the imaging method of choice for evaluating the pediatric thyroid gland, complemented by scintigraphy and thyroid function tests, especially when evaluating children with suspected congenital hypothyroidism, goiter, infectious or autoimmune diseases, or neoplasm. Diagnostic considerations in newborns with congenital hypothyroidism mainly include dysgenesis, dyshormonogenesis, transient hypothyroidism and central (hypophyseal) hypothyroidism. The midline of the neck should be scrutinized for thyroid tissue from the floor of the mouth to the thoracic inlet. Cystic and echogenic ultimobranchial remnants should not be misinterpreted as orthotopic thyroid tissue. Diffuse thyroid diseases affect older children; these comprise Hashimoto and Graves diseases and infectious thyroiditis and exhibit features similar to those in adults. It is important to note that the diffuse sclerosing variant of papillary thyroid cancer can complicate thyroiditis and should not be confused with Hashimoto disease. In children with solid nodules the threshold for fine-needle aspiration biopsy or surgery should be lower compared to adults because of a higher likelihood of malignancy compared with adults. Biopsy should be considered in nodules with suspicious ultrasonographic features, even when smaller than 1 cm. Adult classification systems of thyroid nodules, although useful, are not sufficient to safely discriminate the nodules' likelihood of malignancy in children. We describe key sonographic findings and suggest a standard checklist that might be considered while performing and interpreting thyroid US in neonates and children.

Familial nonmedullary thyroid cancer (FNMTC) constitutes 3-9% of all thyroid cancer cases. FNMTC is divided into two groups: syndromic and nonsyndromic. Nonsyndromic FNMTC is more common as compared with syndromic FNMTC. In syndromic FNMTC, patients are at risk of nonmedullary thyroid cancer (NMTC) and other tumors, and the susceptibility genes are known. In nonsyndromic FNMTC, NMTC is the major feature of the disease and occurs in isolation with an autosomal dominant pattern of inheritance and variable penetrance. New data have emerged on the genetics, clinical characteristics, and outcomes of patients with FNMTC that may have clinical relevance in the management of patients. In this review, we focus on newly characterized syndromic FNMTC entities, criteria for screening and surveillance of nonsyndromic FNMTC, and the classification of nonsyndromic FNMTC as well as the genetic background and heterogeneity of nonsyndromic FNMTC.

Despite the fact that thyroid surgery has evolved towards minimal incisions and endoscopic approaches, the role of total endoscopic thyroidectomy (TET) in thyroid cancer has been highly disputed. We performed a systematic review and meta-analyses of peer reviewed studies in order to evaluate the safety and effectiveness of TET compared with conventional open thyroidectomy (COT) in papillary thyroid cancer (PTC). Medical literature databases such as PubMed, Embase, the Cochrane Library, and Web of science were systematically searched for articles that compared TET and COT in PTC treatment from database inception until March 2019. The quality of the studies included in the review was evaluated using the Downs and Black scale using Review Manager software Stata V.13.0 for the meta-analysis. The systematic review and meta-analysis were based on 5664 cases selected from twenty publications. Criteria used to determine surgical completeness included postoperative thyroglobulin (TG) levels, recurrence of the tumor after long-term follow-up. Adverse event and complication rate scores included transient recurrent laryngeal nerve (RLN) palsy, permanent RLN palsy, transient hypocalcaemia, permanent hypocalcaemia, operative time, number of removed lymph nodes, length of hospital stay and patient cosmetic satisfaction. TET was found to be generally equivalent to COT in terms of surgical completeness and adverse event rate, although TET resulted in lower levels of transient hypocalcemia (OR 1.66; p

To investigate the value of ultrasound (US) and clinicopathological features of papillary thyroid cancer (PTC) in predicting Telomerase Reverse Transcriptase (TERT) promoter mutations. Preoperative US images of 351 surgically confirmed PTCs were evaluated in terms of PTCs size and US features. The basic clinicopathological features were also retrieved. Univariate and multivariate analyses were performed to identify the risk factors for TERT promoter mutations. A scoring system was developed based on the cumulative number of risk factors. The area under the receiver operating characteristic curve (AUC) and cut-off value were calculated to evaluate the diagnostic performance of the scoring system for predicting TERT promoter mutations. TERT promoter mutations were found in 4.84% (17/351) of patients with PTCs. Patient age >50 years (OR: 6.244, P = 0.006), multifocality (OR: 21.071, P = 0.022), taller-than-wide shape (OR: 4.934, P = 0.029), microlobulated margin (OR: 4786, P = 0.032), and capsule contact or involvement (OR: 4.668, P = 0.030) were independent risk factors for TERT promoter mutations. TERT promoter mutations were relevant to more suspicious US and clinicopathological features than TERT promoter wild-type PTC (median, 4 vs. 1, P

Summary Background We evaluated the frequency of incidental papillary thyroid microcarcinomas (mPTC) in thyroidectomies performed for benign diseases, to better characterize this nosologic entity and to assess the best treatment. Methods Between 2009 and 2017, a total of 1777 patients underwent surgery for benign thyroid disease. Patients with preoperative undetermined or positive for malignancy cytology were excluded, as well as incidental thyroid cancer larger than 1 cm. Results Total thyroidectomy was performed in 1649 patients (92.7%) and hemithyroidectomy in 128 (7.2%). Papillary thyroid cancer, sized between 2–10 mm, was found in 89 patients (5%), which were all by definition microcarcinomas (mPTC). In 11 patients mPTCs were multifocal and in 7 bilateral. Just 6 patients received hemithyroidectomy and later underwent radical surgery without complications. No tumor-related morbidity or mortality was observed. The χ2 test showed a statistically significant association between mPTC and non-toxic multinodular goiter. Discussion In the literature, the rates of incidental mPTC vary, due to various factors such as histopathological examination and sampling numbers. Regarding surgical treatment, some authors support a “conservative” approach for the positive prognosis, but considering that it can be associated with mortality, lymph node recurrence and metastasis, its treatment is still controversial. Conclusions Our experience confirms that total thyroidectomy in multinodular goiter is a safe procedure, which ensures endocrine control and oncologic complete tumor resection, in case of mPTC. In uninodular goiter, we recommend hemithyroidectomy; if mPTC is discovered, we suggest radical surgery especially in patients older than 50 years and with familial disposition for thyroid cancer and peripheral tumors larger than 5 mm and aggressive variants.

Identification of stage-specific prognostic/predictive biomarkers in papillary thyroid carcinoma (PTC) could lead to its more efficient clinical management. The main objective of this study was to characterize the stage-specific deregulation in genes and miRNA expression in PTC to identify potential prognostic biomarkers. 495 RNASeq and 499 miRNASeq PTC samples (stage I–IV) as well as, respectively, 56 and 57 normal samples were retrieved from The Cancer Genome Atlas (TCGA). Differential expression analysis was performed using DESeq 2 to identify deregulation of genes and miRNAs between sequential stages. To identify the minority of patients who progress to higher stages, we performed clustering analysis on stage I RNASeq data. An independent PTC RNASeq data set (BioProject accession PRJEB11591) was also used for the validation of the results. LTF and PLA2R1 were identified as two promising biomarkers down-regulated in a subgroup of stage I (both in TCGA and in the validation data set) and in the majority of stage IV of PTC (in TCGA data set). hsa-miR-205, hsa-miR-509-2, hsa-miR-514-1 and hsa-miR-514-2 were also detected as up-regulated miRNAs in both PTC patients with stage I and stage III. Hierarchical clustering of stage I samples showed substantial heterogeneity in the expression pattern of PTC indicating the necessity of categorizing stage I patients based on the expressional alterations of specific biomarkers. Stage I PTC patients showed large amount of expressional heterogeneity. Therefore, risk stratification based on the expressional alterations of candidate biomarkers could be an important step toward personalized management of these patients.

Whether chronic lymphocytic thyroiditis (CLT) influences the risk of development and the progression of papillary thyroid cancer (PTC) remains uncertain. We investigated the effects of CLT on the clinicopathologic features and prognosis of PTC. Two thousand nine hundred twenty-eight consecutive patients with PTC treated between 2009 and 2017 were divided into two groups: one with chronic lymphocytic thyroiditis and one without; 1174 (40%) of the patients had coincident CLT. In univariate analysis, CLT correlated positively with small tumor size, frequent extrathyroidal extension, multifocal diseases, and p53 but negatively with central lymph node (LN) metastasis and BRAF mutation. In multivariate analysis, CLT was associated with extrathyroidal extension and multifocal disease; however, it was not a prognostic factor for recurrence even though it was associated with two aggressive factors. Compared with patients with PTC alone, there were more retrieved central LNs in the PTC + CLT group, and these patients also underwent more invasive diagnostic tests such as fine needle aspiration cytology and frozen biopsy of LN. The CLT patients with PTC had better behavior features and prognoses than did those with PTC alone despite frequent multifocality and extrathyroidal extension. However, precaution may be necessary to avoid performing invasive diagnostic procedures for lateral LN metastasis and to manage the patients appropriately.

Injection of carbon nanoparticle (CN) into the thyroid gland is used to stain CLNs in endoscopic surgery of patients with papillary thyroid cancer (PTC). The black-dye technique facilitates the central lymph nodes (CLNs) harvest and parathyroid protection, but improper handling of CN during injection leads to unwanted staining of surrounding tissues and increases the difficulty in anatomical identification. Therefore, a new method is needed to overcome this problem. Forty-eight patients with PTC underwent endoscopic thyroidectomy via breast approach. Patients were randomized into the indocyanine green (ICG) group (Group ICG; n = 23) and CN group (Group CN; n = 25). After thyroid gland exposure, ICG was injected into the thyroid lobes. Fluorescent CLNs were identified and dissected in Group ICG. In Group CN, CN was used instead. Black dyed CLNs were harvested. The following was compared between groups: demographic characteristics, surgical time, drainage amount, hospital stay duration, number of CLNs harvested, frequency of postoperative hoarseness and hypothyroidism, and surgical cost. Group ICG showed decreased hypoparathyroidism frequency than Group CN (1/23 vs. 7/25, p = 0.028) and more harvested CLNs (4.6 ± 1.0 vs. 3.8 ± 1.2, p = 0.020). There was no difference between drainage amount, hospital stay duration, and frequency of postoperative hoarseness. The cost of Group ICG was less than that of Group CN (p = 0). Injection of ICG into the thyroid gland using fluorescence imaging in endoscopic surgery in patients with PTC is safer and more effective in identifying CLNs than injection with CN. This novel method can lead to improved identification and subsequent harvesting of CLNs.

Most patients with papillary thyroid cancer (PTC) and lymph node metastases (LNM) undergoing reoperation do not show apparent disease after this procedure, but serum thyroglobulin (Tg) continues to be elevated in part of them. This study evaluated adjuvant therapy with 131I in these patients. Patients with PTC and LNM diagnosed after initial therapy were selected. Patients undergoing reoperation and those without apparent disease after this procedure, but with nonstimulated Tg ≥1 ng/ml 6 months after reoperation, were included. The first 25 patients were submitted to therapy with 131I (groups A) and the subsequent 30 patients did not receive this therapy (group B). Groups A and B were similar. During further follow-up, 21 patients developed structural disease and 34 continued without detectable disease (eight achieved complete remission). The outcomes were similar in groups A and B. Patients with Tg reduction >50% after reoperation tended to have a lower risk of recurrence (22.7 versus 48.5%), notably distant metastases (0 versus 15.1%), and were more likely to achieve complete remission (28 versus 3%). Patients with LNM FDG-positive had a higher risk of recurrence (54.5 versus 11.7%) and were less likely to achieve complete remission (3 versus 29.4%) after reoperation. Our results suggest that therapy with 131I apparently does not prevent recurrences among patients who continue to have elevated Tg after neck reoperation. Further studies involving these patients are necessary, especially those who are at high risk of recurrence.

The BRAFV600E mutation is the most prevalent genetic event in patients with papillary thyroid cancer (PTC). However, no study has investigated the expression of PAQR3 in papillary thyroid tissues in relation to the BRAFV600E mutation and the clinicopathological features of PTC patients. Furthermore, the potential associations of the BRAFV600E mutation, PAQR3 expression and clinicopathological parameters in the cancerous tissues of PTC patients have not been investigated. This study was conducted on 60 patients with PTC who were treated surgically at our institution from 2017 to 2018. PCR was used to amplify DNA by the amplification refractory mutation system (ARMS) method to detect BRAFV600E gene mutations. In addition, immunohistochemical techniques were utilized to assess PAQR3 expression in tumor tissue sections. The BRAFV600E mutation was associated with lymph node metastasis (LNM, p

Transoral endoscopic thyroidectomy vestibular approach (TOETVA) has been widely accepted in the treatment of papillary thyroid cancer. However, TOETVA for the treatment of medullary thyroid carcinoma (MTC) has not been reported. We successfully performed total thyroidectomy and central neck dissection by TOETVA for a MTC patient and have achieved satisfactory surgical outcomes in short-term follow-up. This is the first report on TOETVA for the treatment of MTC and it may provide an alternative for cT1N0M0 MTC patients who desire better cosmetic surgical outcomes.

Merkel cell polyomavirus (MCPyV) infects most people asymptomatically, but recent reports indicate that the virus may be related to carcinogenesis. This study aimed to evaluate the impact of MCPyV on the development of papillary thyroid cancer (PTC). Totally, 1057 samples, including 412 fresh biopsy samples (FBS) and 645 paraffin-embedded PTC biopsy samples (PEBS), and 1057 adjacent non-cancerous samples were assessed for the presence of MCPyV DNA and RNA. MCPyV DNA was positive in 215 (20.3%) of samples, including 126 (30.6%) in FBS and 89 (13.8%) in PEBS. In MCPyV-positive samples, the mean MCPyV copy number was higher in the patients with FBS (2.3 × 10–1 ± 0.5 × 10–1 copies/cell) compared to PEBS (0.7 × 10–4 ± 0.1 × 10–4 copies/cell) and adjacent non-PTC normal samples (0.3 × 10–5 ± 0.02 × 10–5 copies/cell), indicating a statistically significant difference (P LT-Ag RNA expression was higher in FBS compared to PEBS, while VP1 gene transcript was not detected in any samples. Although our findings showed the presence of MCPyV in a subset of PTC Iranian patients, further research is required to confirm these findings.

Lactate dehydrogenase A (LDHA), a critical component of the glycolytic pathway, relates to the development of various cancers, including thyroid cancer. However, the regulatory mechanism of LDHA inhibition and the physiological significance of the LDHA inhibitors in papillary thyroid cancer (PTC) are unknown. Long non-coding RNA (lncRNA) plays a vital role in tumor growth and progression. Here, we identified a novel lncRNA LINC00671 negatively correlated with LDHA, downregulating LDHA expression and predicting good clinical outcome in thyroid cancer. Moreover, hypoxia inhibits LINC00671 expression and activates LDHA expression largely through transcriptional factor STAT3. STAT3/LINC00671/LDHA axis regulates thyroid cancer glycolysis, growth, and lung metastasis both in vitro and in vivo. In thyroid cancer patients, LINC00671 expression is negatively correlated with LDHA and STAT3 expression. Our work established STAT3/LINC00671/LDHA as a critical axis to regulate PTC growth and progression. Inhibition of LDHA or STAT3 or supplement of LINC00671 could be potential therapeutic strategies in thyroid cancer.