Aggressive Papillary Thyroid Cancer Research Articles

Analyzing the correlation between low proportion of hobnail features in papillary thyroid carcinoma and clinical aggressiveness risk.

Hobnail features may enhance the clinical aggressiveness of papillary thyroid carcinoma (PTC). However, whether a low proportion (<30%) of these features contributes to increased PTC aggressiveness remains unclear. This study investigated whether PTC cases with a low proportion hobnail features (<30%) exhibit clinical invasiveness and pathological features of aggressiveness. Pathological specimens from patients with postoperatively diagnosed PTC were retrospectively analyzed. Among them, 29 PTC cases with a low proportion of hobnail features (<30%) were compared with 173 consecutive classical PTC (cPTC) cases. Data regarding age at presentation, sex, tumor size, number of tumors, and histological characteristics were obtained by reviewing electronic medical records. Postoperative information was obtained during follow-up visits and telephone interviews. Twenty-nine patients with PTC with a low proportion of hobnail features (<30%) were identified, exhibiting a median age of 34 years. At a median follow-up of 31 (IQR, 23-37) months, two patients had recurrent disease in the PTC with a low proportion of hobnail features (<30%) group, whereas there was no recurrence in the cPTC group. No distant metastasis and postoperative mortality were observed in either group. Compared with the cPTC group, patients with PTC and a low proportion of hobnail features exhibited larger tumor volumes and higher susceptibility to capsular invasion and lymph node metastasis. Tumor size and hobnail features emerged as independent risk factors for lymph node metastasis. PTC with a low proportion hobnail features (<30%) and larger tumor volumes are associated with the occurrence of lymph node metastasis. A low proportion of hobnail features (<30%) in PTC may heighten invasiveness, elevating the risk of recurrence.

Hsa_circ_0101050 regulated by ZC3H13 enhances tumorigenesis in papillary thyroid cancer via m6A modification

While the regulatory roles of circular RNAs (circRNAs) and zinc finger CCCH-type containing 13 (ZC3H13) were previously reported in various human cancers, the mechanisms underlying their interaction in papillary thyroid cancer (PTC) remain unclear. We aimed to determine the role of hsa_circ_0101050 and its regulatory relationship with ZC3H13 in PTC. The expression levels of hsa_circ_0101050 and ZC3H13 were determined in tumor samples and adjacent normal tissues from 46 patients with PTC and in two PTC cell lines (IHH-4 and PTC-1) using quantitative reverse transcription–polymerase chain reaction. The roles of hsa_circ_0101050 and ZC3H13 in cell viability, wound healing, and migration were determined using knockdown and overexpression approaches in PTC cell lines, and a xenograft model in nude mice was used to determine their role in vivo. Methylated RNA immunoprecipitation assay was used to analyze N6-methyladenosine (m6A) modification of hsa_circ_0101050 by ZC3H13. We found hsa_circ_0101050 overexpression and ZC3H13 downregulation in PTC samples and PTC cell lines. In PTC cell lines, silencing hsa_circ_0101050 reduced cell viability and migration whereas its overexpression promoted an aggressive PTC phenotype. ZC3H13 increased the m6A modification of hsa_circ_0101050 and repressed its expression. ZC3H13 overexpression inhibited PTC cell viability, migration, and invasion, which were reversed in cells overexpressing hsa_circ_0101050. Taken together, these results suggested that the downregulation of hsa_circ_0101050 mediated by ZC3H13 through m6A modification contributed to its oncogenic effect in PTC development, revealing the ZC3H13–m6A–hsa_circ_0101050 as a potential therapeutic target in PTC.

Correlation analysis between BRAFV600E mutation and ultrasonic and clinical features of papillary thyroid cancer

PurposeThe study investigates the value of the BRAFV600E mutation in determining the aggressiveness of papillary thyroid cancer (PTC) and its correlation with ultrasound features. MethodsThe study selected 176 patients with BRAFV600E mutation and 80 without the mutation who underwent surgery at Guangxi Medical University Cancer Hospital. Clinical and pathological data were collected, focusing on BRAFV600E mutations and associated ultrasonic features. Correlation analysis, as well as univariate and multivariate logistic regression analysis, were conducted to identify independent risk factors for BRAFV600E mutation. The results were verified using a nomogram model. ResultsThe analysis results indicate that the BRAFV600E mutation correlates with tumor size, nodule size, taller-than-wide shape, margin, and shape of papillary thyroid cancer. The receiver operating characteristic curve was used to analyze the diagnostic effect of these features on BRAFV600E mutation. The results showed that nodule size had the most significant area under the curve (AUC = 0.665). Univariate and multivariate logistic regression analyses revealed that taller-than-wide shape ≥1, ill-defined margin, irregular shape, nodule size (≤1.40 cm), TT4 (>98.67 nmol/L), and FT3 (<4.14 pmol/L) were independent risk factors for BRAFV600E mutation. While considering all these factors in the nomogram, the Concordance index (C-index) remained high at 0.764. This suggests that the model has a good predictive effect. ConclusionUltrasound features including nodule size, taller-than-wide shape ≥1, ill-defined margins, irregular shape, higher TT4 levels, and lower FT3 levels were associated with papillary thyroid cancer aggressiveness and BRAFV600E mutation.

Dihydrotanshinone I exhibits antitumor effects via β-catenin downregulation in papillary thyroid cancer cell lines

Thyroid cancer is the most common endocrine carcinoma and, among its different subtypes, the papillary subtype (PTC) is the most frequent. Generally, PTCs are well differentiated, but a minor percentage of PTCs are characterized by a worse prognosis and more aggressive behavior. Phytochemicals, naturally found in plant products, represent a heterogeneous group of bioactive compounds that can interfere with cell proliferation and the regulation of the cell cycle, taking part in multiple signaling pathways that are often disrupted in tumor initiation, proliferation, and progression. In this work, we focused on 15,16-dihydrotanshinone I (DHT), a tanshinone isolated from Salvia miltiorrhiza Bunge (Danshen). We first evaluated DHT biological effect on PTC cells regarding cell viability, colony formation ability, and migration capacity. All of these parameters were downregulated by DHT treatment. We then investigated gene expression changes after DHT treatment by performing RNA-seq. The analysis revealed that DHT significantly reduced the Wnt signaling pathway, which plays a role in various diseases, including cancer. Finally, we demonstrate that DHT treatment decreases protein levels of β-catenin, a final effector of canonical Wnt signaling pathway. Overall, our data suggest a possible use of this nutraceutical as an adjuvant in the treatment of aggressive papillary thyroid carcinoma.

Abstract 6277: Tall cell variant papillary thyroid carcinoma from Middle Eastern patients have worse outcome than classical papillary thyroid carcinoma using propensity score matching

Abstract The tall cell variant of Papillary Thyroid Carcinoma (TCV-PTC) is the most common aggressive variant of PTC. The impact of TCV-PTC on patients’ prognosis still remains controversial. Moreover, the clinico-pathological and prognostic effect of TCV-PTC from Middle Eastern ethnicity remains unexplored. We aimed to study TCV-PTC in comparison to classical PTC in Middle Eastern patients and their impact on prognosis. We performed a retrospective cohort study of tall cell variant (TCV-PTC) and classic variant of papillary thyroid carcinoma (CV-PTC) after post-surgical radioactive iodine therapy. We used the propensity score matching (1:3 matching ratio) to account for differences between recipients of TCV-PTC vs CV-PTC. Univariate and multivariate analysis were performed to assess the independent factors for persistent/recurrent disease. Kaplan-Meier curve analyses were used to compare disease-free survival (DFS). In total, 174 (16.3%) patients with TCV-PTC and 891 (83.7%) patients with CV-PTC were included. After propensity score matching, 174 pairs of patients were selected (TCV-PTC, n = 174; CV-PTC, n = 522). In the matched analysis, higher proportions of TCV-PTC experienced persistent/recurrent disease compared with CV-PTC (25.7% vs 31.4%; p = 0.0119). In multivariate analyses of clinical and tumor characteristics, histological type of TCV-PTC (odds ratio, 2.09; 95% confidence interval, 1.28-3.40; p = 0.0031) was associated with increased risk of persistent/recurrent disease. The five-year DFS rates for the TCV-PTC and CV-PTC groups were 48.5% and 73.1%, respectively. The Kaplan- Meier analysis indicated that the TCV-PTC group (p &amp;lt; 0.0001) had shorter DFS. In conclusion, when other clinico-pathological factors were similar, this propensity score matched analysis showed that histological subtype TCV-PTC is by itself an independent predictive marker of persistent/recurrent disease in Middle Eastern patients. Therefore, individualized therapeutic approaches might be needed for this aggressive PTC subtype. Citation Format: Khawla S. Al-Kuraya, Sandeep K. Parvathareddy, Abdul K. Siraj, Saeeda O. Ahmed, Nabil Siraj, Manal Manakhan, Hassan Aldossari. Tall cell variant papillary thyroid carcinoma from Middle Eastern patients have worse outcome than classical papillary thyroid carcinoma using propensity score matching [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6277.

Papillary Thyroid Cancer Trends in the Wake of the COVID-19 Pandemic: Is There a Shift toward a More Aggressive Entity?

Globally, the incidence of papillary thyroid cancer (PTC) has been increasing over the last few decades and it has become the second most common cancer in women in the UAE. There is some evidence to suggest that COVID-19 infection might be directly linked to the development of aggressive variants of PTC. The primary goal of this study was to compare the clinical and pathologic characteristics of thyroid cancer patients treated at the largest endocrine surgery center in Abu Dhabi before and after the COVID-19 pandemic outbreak. This retrospective cohort analysis included patients who underwent elective thyroid surgery at Burjeel Hospital between January 2018 and December 2022. Patients were divided into two groups based on when the COVID-19 outbreak started: group one, comprising patients who had surgery between January 2018 and December 2019 (the "pre-pandemic group"), and group two, comprising patients who had surgery between January 2021 and December 2022 (the "post-pandemic group"). In addition to demographic data, clinicopathological factors, such as aggressive cell type, multifocality, tumor size and location, laterality, lympho-vascular invasion, and extrathyroidal extension, were assessed. We utilized the t-paired test for parametric variables and the Chi-square test for the cross-table analysis. During the study, 1141 people had thyroid surgery, with an annual average of 285 procedures. PTC cases recorded in the final histopathological samples rose from 111 in the pre-pandemic era to 182 in the post-pandemic era. Neither the female-to-male gender ratio, which was 90:21 in the pre-pandemic group and 142:40 in the post-pandemic group (p = 0.532), nor the median age, which was 39.1 and 40.1 years, respectively, varied significantly between the two groups. However, there was a significant increase between pre-pandemic and post-pandemic in the aggressive PTC variants (3% vs. 11.5%, p = 0.001), increased poor prognostic factors such as bilateral multifocality (10.8% vs. 32.4%, p = 0.000), as well as increased capsule-vascular tumor invasion (19.8% vs. 27%); on the other hand, the size of the single foci was 17 mm in the pre-pandemic group compared to 13 mm in the post-pandemic group (p = 0.001). A significant rise in unfavorable prognostic markers and aggressive subtypes of PTC was seen post-pandemic in thyroidectomy patients operated on at a leading endocrine surgery center in the United Arab Emirates.

Association of BRAF V600E Mutant Allele Proportion with the Dissemination Stage of Papillary Thyroid Cancer.

The early identification of aggressive forms of cancer is of high importance in treating papillary thyroid cancer (PTC). Disease dissemination is a major factor influencing patient survival. Mutation status of BRAF oncogene, BRAF V600E, is proposed to be an indicator of disease recurrence; however, its influence on PTC dissemination has not been deciphered. This study aimed to explore the association of the frequency of BRAF V600E alleles in PTC with disease dissemination. In this study, 173 PTC samples were analyzed, measuring the proportion of BRAF V600E alleles by qPCR, which was then normalized against the proportion of tumor cells. Semiquantitative analysis of BRAF V600E mutant protein was performed by immunohistochemistry. The BRAF V600E mutation was present in 60% of samples, while the normalized frequency of mutated BRAF alleles ranged from 1.55% to 92.06%. There was no significant association between the presence and/or proportion of the BRAF V600E mutation with the degree of PTC dissemination. However, the presence of the BRAF mutation was significantly linked with angioinvasion. This study's results suggest that there is a heterogeneous distribution of the BRAF mutation and the presence of oligoclonal forms of PTC. It is likely that the BRAF mutation alone does not significantly contribute to PTC aggressiveness.

Elevated Levels of Interleukin-18 are Associated with Lymph Node Metastasis in Papillary Thyroid Carcinoma.

Interleukin-18 (IL-18) is a proinflammatory cytokine that primarily stimulates the Th1 immune response. IL-18 exhibits anticancer activity and has been evaluated in clinical trials as a potential cancer treatment. However, evidence suggests that it may also facilitate the development and progression of some cancers. So far, the impact of IL-18 on papillary thyroid cancer (PTC) has not been investigated. In this study, we found that the expression of IL-18 was significantly increased in PTC compared to normal thyroid tissue. Elevated IL-18 expression was closely associated with lymphovascular invasion and lymph node metastases. Furthermore, compared to PTC patients with no nodal metastasis, serum IL-18 levels were slightly increased in patients with 1-4 nodal metastases and significantly elevated in patients with 5 or more nodal metastases. The pro-metastatic effect of IL-18 may be attributed to the simultaneous increase in the expression of S100A10, a known factor that is linked to nodal metastasis in PTC. In addition, the activation of several pathways, such as the intestinal immune network for lgA production and Staphylococcus aureus infection, may be involved in the metastasis process. Taken together, IL-18 may trigger pro-metastatic activity in PTC. Therefore, suppressing the function of IL-18 rather than enhancing it appears to be a reasonable strategy for treating aggressive PTC.

Minimal Extrathyroid Extension (mETE) as the Only Risk Factor in Patients with Papillary Thyroid Carcinoma (PC): Its Clinical Impact on Recurrence and Outcome during Long-Term Follow-Up.

Minimal extrathyroid extension (mETE) effect on papillary thyroid carcinoma (PC) prognosis is still debated even more so now that this factor has been removed in the 8th AJCC Edition, supporting the hypothesis that mETE is not associated with aggressive tumors. We retrospectively enrolled 91 PC patients (Group 1) submitted to total thyroidectomy and radioiodine ablation. At the time of the primary tumor surgery, mETE was ascertained in all patients with no other risk factors, such as multifocality, vascular invasion, neck and distant metastases, and aggressive histological variants. As controls, 205 consecutive matched PC patients (Group 2) without mETE and the aforementioned risk factors were enrolled. During the follow-up (average 8 years), 16/91 (17.58%) Group 1 patients and 15/205 (7.32%) Group 2 patients developed metastases (p = 0.0078). Cox regression analysis showed an increased risk of metastases in patients with mETE (HR: 2.58 (95% CI 1.28-5.22) p = 0.008). Disease-free survival (DFS) was significantly lower in patients with mETE than in controls (p = 0.0059). The present study seems to demonstrate that mETE can be associated with an aggressive PC and can be considered, even alone without other risk factors, an independent factor of unfavorable DFS. Thus, by excluding mETE in the 8th AJCC Edition, patient care and management could be compromised.

Clinical and morphological features and unsolved issues in diagnosis of aggressive forms of papillary thyroid carcinoma

Differentiated thyroid cancer (DTC) is a disease with a favorable clinical course and high survival rate compared to other epithelial tumors. The majority of DTC (up to 85 %) is represented by various subtypes of papillary thyroid cancer (PTC). Aggressive forms of PTC characterized by early lymphogenous and hematogenous metastasis, low avidity to radioiodine therapy (RIT), low relapse-free survival rates and high mortality rate compared to other types of PTC occur among them. Preoperative diagnosis of PTC is based on the results of ultrasound (US) examination and fine-needle aspiration biopsy (FNA) with cytological examination of the aspirate. At the same time, the capabilities of cytological examination in determining the histological type of PTC are limited and it does not allow to predict its aggressiveness and plan adequate treatment. Molecular genetic tests of the tumor cytological and morphological material are effective in prognosis of aggressiveness of PTC due to the determination of specific mutations in the BRAF, TERT, RAS genes and the quantitative expression of oncogenic and tumor suppressive microRNAs. Some of these indicators are already used in the morphological classification of tumors of the endocrine system.&#x0D; At the same time, there are contradictory data concerning the connection of the molecular genetic portrait of PTC, the clinical manifestations of its aggressiveness (extrathyroidal invasion, early metastasis, and radioiodine resistance) and its pathomorphological structure. We tried to summarize and analyze the literature data regarding the diagnosis of aggressive variants of PTC.

High rates of aggressive features in young Vietnamese females with papillary thyroid carcinoma: Associations with preoperative risk factors

Background: Thyroid carcinoma represents a significant global health burden, rising worldwide incidence. Papillary thyroid carcinoma (PTC) accounts for most cases, but aggressive variants with capsular invasion and nodal metastases require more intensive treatment. Reported rates of these capsular invasion and cervical lymph node metastasis vary widely. This study aimed to elucidate associations between clinical/tumor characteristics, capsular invasion, and nodal metastasis in Vietnamese PTC patients. Methods: This retrospective cohort study examined 1626 patients with cytologically/histologically confirmed thyroid carcinoma at a referral center in Vietnam during 2018–2020. Data collected included demographics, imaging, cytology, tumor features, capsular invasion, and nodal metastasis. Associations were analyzed using chi-squared tests and binary logistic regression. Results: Most patients were young (≤ 45) females with small papillary carcinomas. High rates of capsular invasion (58.7%) and nodal metastasis (28.5%) were observed. Capsular invasion was associated with higher TIRADS categories, Bethesda cytological categories, larger tumors, and papillary histology. Nodal metastasis was linked to younger age, male sex, higher TIRADS categories, larger tumors, papillary histology, and capsular invasion. Binary logistic regression identified TIRADS categories, Bethesda cytological categories, larger tumor size, younger age, male sex, and capsular invasion as independent predictors. Conclusion: Unexpectedly high rates of capsular invasion and cervical lymph node metastasis were found. TIRADS, Bethesda system, tumor size, age, sex, and capsular invasion were significant preoperative risk factors for aggressive PTC behaviors.

Sex-dependent impact of obesity on aggressiveness of papillary thyroid cancer.

To investigate the impact of body mass index (BMI) on the aggressiveness of papillary thyroid cancer (PTC). A total of 1720 PTC patients with total thyroidectomy or lobectomy, from January 2017 to April 2020, were retrospectively evaluated. Based on BMI, they were divided into two groups, as follows: control (CON, < 24 kg/m2) and overweight and obesity (OB, ≥ 24 kg/m2), each sex being analyzed separately. In the whole cohort, the OB group had significantly higher rates of extrathyroidal extension (21.5 vs. 16.8%, p = 0.013), multifocality (43.2 vs. 37.7%, p = 0.018), and BRAF-V600E mutation (82.9 vs. 79.3%, p = 0.015) than the CON group. In males, the OB group had increased rates of tumor size over 1cm (54.4 vs. 42.7%, p = 0.008), extrathyroidal extension (24.9 vs. 12.4%, p = 0.001), and multifocality (42.7 vs. 33.5%, p = 0.038). The OB group had significantly higher adjusted odds ratios (ORs) of 1.63 (1.14-2.33, p = 0.008), 2.12 (1.26-3.57, p = 0.005), and 1.56 (1.07-2.29, p = 0.022) for tumor size over 1cm, extrathyroidal extension, and multifocality compared with CON. Additionally, overweight and obesity were analyzed alone and the rates of extrathyroidal extension (30/100, 30.0%, p = 0.001) and tumor size over 1cm (65/100, 65.0%, p = 0.001) were significantly higher in the obesity group than in the overweight and CON groups. The obesity group had robust higher adjusted ORs of 2.51(1.50-4.20, p < 0.001), 2.93 (1.50-5.73, p = 0.002) and 1.89 (1.11-3.22, p = 0.020) for tumor size over 1cm, extrathyroidal extension, and multifocality compared with CON. Overweight and obesity were predominant independent risk factors for PTC aggressiveness in males. These data indicated that the therapeutic treatment should be based on risk stratification by BMI in males.

Genetic trio of BRAF and TERT alterations and rs2853669TT in papillary thyroid cancer aggressiveness.

BRAF V600E and TERT promoter alterations are core components in current genetics-based risk assessment for precision management of papillary thyroid cancer. It remains unknown whether this approach could achieve even better precision through a widely recognized prognostic single-nucleotide variation (SNV, formerly SNP), rs2853669T>C, in the TERT promoter. The genetic status of alterations and SNV were examined by sequencing genomic DNA from papillary thyroid cancer in 608 patients (427 women and 181 men) aged 47 years (interquartile range = 37-57), with a median follow-up time of 75 months (interquartile range = 36-123), and their relationship with clinical outcomes was analyzed. A luciferase reporter assay was performed to examine TERT promoter activities. TERT promoter alterations showed a strong association with papillary thyroid cancer recurrence in the presence of genotype TT of rs2853669 (adjusted hazard ratio [HR] = 2.12, 95% confidence interval [CI] = 1.10 to 4.12) but not TC/CC (adjusted HR = 1.17, 95% CI = 0.56 to 2.41). TERT and BRAF alterations commonly coexisted and synergistically promoted papillary thyroid cancer recurrence. With this genetic duet, TT of rs2853669 showed a robustly higher disease recurrence than TC/CC (adjusted HR = 14.26, 95% CI = 2.86 to 71.25). Patients with the genetic trio of BRAF V600E, TERT alteration, and TT of rs2853669 had a recurrence of 76.5% vs recurrence of 8.4% with neither variation and with TC/CC (HR = 13.48, 95% CI = 6.44 to 28.21). T allele of rs2853669 strongly increased TERT promoter activities, particularly the variant promoters. The SNV rs2853669T>C dramatically refines the prognostic power of BRAF V600E and TERT promoter alterations to a higher precision, suggesting the need for including this SNV in the current genetics-based risk prognostication of papillary thyroid cancer.

Prevalence of Differentiated High-Grade Thyroid Carcinoma Among Well-Differentiated Tumors: A Systematic Review and Meta-Analysis.

Background: The current edition of the World Health Organization (WHO) classification of endocrine tumors introduced grading for follicular cell-derived thyroid cancer. Tumors with necrosis and/or high mitotic count but not fulfilling the Turin criteria for poorly differentiated carcinoma will be reclassified as differentiated high-grade thyroid carcinoma (DHGTC). However, the impact of this reclassification has not been evaluated. In this study, we performed a systematic review and meta-analysis to estimate the prevalence of this new entry across thyroid tumor subtypes. Methods: In this systematic review and meta-analysis, studies reporting data on necrosis and/or mitoses in well-differentiated thyroid carcinoma (WDTC) were used to estimate the prevalence of DHGTC. Heterogeneity and potential publication bias were also evaluated. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed, and quality assessment was performed using a modification of the Newcastle-Ottawa scale. The study has been registered in the International Prospective Register of Systematic Reviews (PROSPERO, ID: CRD42022378716). Results: In clinically unselected patients, the prevalence of DHGTC in WDTC was 0.072 [95% confidence interval, CI, = 0.045-0.113]. The proportion of high-grade tumors greatly varied across growth patterns and subtypes. Overall, the prevalence of DHGTC was higher in follicular thyroid carcinoma (FTC; 0.146 [CI = 0.101-0.205]) than in papillary thyroid carcinoma (PTC; 0.059 [CI = 0.036-0.097]). Diffuse sclerosing, follicular, and classic subtype PTC had the lowest rates of high-grade features (i.e., 0.018 [CI = 0.004-0.084]; 0.036 [CI = 0.010-0.124]; and 0.042 [CI = 0.027-0.066], respectively), while a greater proportion of solid trabecular and histologically aggressive PTC could be reclassified as DHGTC (i.e., 0.154 [CI = 0.067-0.314] and 0.168 [CI = 0.108-0.252], respectively). Similar proportions were obtained for minimally and widely invasive FTC (i.e., 0.136 [CI = 0.058-0.287] and 0.152 [CI = 0.086-0.254], respectively). Finally, in a cohort of patients with poor prognosis (i.e., fatal cases, metastatic and radioiodine resistant tumors, cases with biochemical recurrence), the proportion of DHGTC was 0.287 [CI = 0.155-0.469]. Conclusions: Following the current WHO indications, some tumors will be reclassified as DHGTC. The proportion of tumors with high-grade features is relevant in FTC, solid trabecular, and histologically aggressive PTC subtypes. A remarkable enrichment in DHGTC among patients with poor prognosis confirms the negative impact of high-grade features on outcome.

BRAFV600E, BANCR, miR-203a-3p and miR-204-3p in Risk Stratification of PTC Patients.

In order to enhance the risk stratification of papillary thyroid carcinoma (PTC) patients, we assessed the presence of the most common mutation in PTC (BRAFV600E) with the expression profiles of long non-coding RNA activated by BRAFV600E (BANCR) and microRNAs, which share complementarity with BANCR (miR-203a-3p and miR-204-3p), and thereafter correlated it with several clinicopathological features of PTC. BRAFV600E was detected by mutant allele-specific PCR amplification. BANCR and miRs levels were determined by quantitative RT-PCR. Bioinformatic analysis was applied to determine the miRs' targets. The expression profile of miR-203a-3p/204-3p in PTC was not affected by BRAFV600E. In the BRAFV600E-positive PTC, high expression of miR-203a-3p correlated with extrathyroidal invasion (Ei), but the patients with both high miR-203a-3p and upregulated BANCR were not at risk of Ei. In the BRAFV600E-negative PTC, low expression of miR-204-3p correlated with Ei, intraglandular dissemination and pT status (p < 0.05), and the mutual presence of low miR-204-3p and upregulated BANCR increased the occurrence of Ei. Bioinformatic analysis predicted complementary binding between miR-203a-3p/204-3p and BANCR. The co-occurrence of tested factors might influence the spreading of PTC. These findings partially describe the complicated network of interactions that may occur during the development of PTC aggressiveness, potentially providing a new approach for high-risk PTC patient selection.

Prediction of classical versus non classical papillary thyroid carcinoma subtypes from cytology of nodules classified according to TIRADS

PurposeOur purposes were: 1) to estimate the prediction performance (PP) of cytology in identifying papillary thyroid carcinoma (PTC) subtypes; 2) to explore how the PTC subtypes distribute among the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) categories.MethodsNodules were included if both the histology with the PTC subtype report and the cytology report with the possible PTC subtype were available. The PP was calculated by making the proportion of True positives/False positives+false negatives.Results309 cytologically “suspicious for malignancy” and “malignant” thyroid nodules with PTC histology were evaluated. ACR TI-RADS categorization for classical PTC was significantly different from non-classical PTC (p-value 0.02). For the whole cohort the PP of cytologically classical cases was 0.74, while that of cytologically non classical cases was 0.41. ACR TI-RADS categorization was not significantly different for aggressive vs non-aggressive PTC subtypes (p-value 0.1). When considering only aggressive or non-aggressive PTC subtypes, the PP of cytologically classical cases was respectively 0.86 and 0.87, while that of cytologically non classical cases was respectively 0.27 and 0.22. The PP of cytologically classical cases was 0.73 and 0.79, respectively for macroPTCs and microPTCs, while that of cytologically non classical cases was 0.55 and 0.33, respectively for macroPTCs and microPTCs.ConclusionCytology examination reliably performed in predicting classical PTC versus non classical PTC subtypes. ACR TI-RADS categorization was significantly different among classical PTC versus non classical PTC subtypes.

Association of serum 25-hydroxyvitamin D levels with aggressiveness of papillary thyroid cancer.

Serum 25-hydroxyvitamin D (25(OH)D) deficiency has been known to be associated with the risk and mortality of several cancers. However, the role of 25(OH)D in papillary thyroid cancer (PTC) remains controversial. This study aimed to investigate the association between 25(OH)D and clinicopathologic features of PTC. Patients who underwent thyroidectomy were retrospectively reviewed. Serum 25(OH)D levels were measured within a week prior to surgery. The patients were categorized into four quartiles according to season-specific 25(OH)D levels. The association between 25(OH)D levels and clinicopathologic features of PTC was analyzed. A total of 2932 patients were enrolled in the study. The 25(OH)D levels were significantly higher in patients with lymph node metastasis (LNM; P < 0.001), lateral LNM (P < 0.001), and multifocal tumors (P < 0.001). Compared to the first quartile (Q1) of 25(OH)D level, the third quartile (Q3) and the fourth quartile (Q4) showed an unadjusted OR of 1.36 (95% CI: 1.09-1.69; P = 0.006) and 1.76 (95% CI: 1.42-2.19; P < 0.001) for LNM (P for trend < 0.001), respectively. An increased risk of multifocal tumors was strongly associated with high 25(OH)D concentration (P for trend <0.001). Similar results were obtained after adjusting for confounding factors. High 25(OH)D levels are associated with aggressive features of PTC, such as lymph node metastasis and multifocality.

The BRAFV600E mutation maintains the aggressiveness of papillary thyroid cancers requiring downregulation of primary cilia

Although disorders of primary cilia (PCs) were first reported in human papillary thyroid cancer (PTC) tissues in 1987, their precise role in PTC remains unclear. PCs sense the thyroid follicle colloid environment and act as a cell signaling hub. The present study investigated whether PCs are needed for BRAFV600E-driven PTC. We assessed whether BRAFV600E protein expression correlates with papillary histological architecture and clinicopathological features of PTC. We found that expression of ciliary intraflagellar transport 88 (IFT88) and PC formation were reduced in BRAFV600E-driven PTCs and that loss of cilia may be associated with lymph node metastasis. In PTC cells, the BRAFV600E mutation maintained the aggressiveness of PTC, which was partially related to loss of PCs. Our work confirms that BRAFV600E mutation-driven PC downregulation contributes to maintaining the aggressiveness of PTCs and that manipulating PC can potentially reduce the adverse incidence of PTC in a range of conditions.

BRAFV600E Positivity-Dependent Effect of Age on Papillary Thyroid Cancer Recurrence Risk.

BRAFV600E positivity is associated with increased aggressiveness of papillary thyroid cancer (PTC), and age is an important prognostic factor. However, the association between age and BRAFV600E positivity and the recurrence risk has not been investigated. This study aimed to investigate the impact of age on recurrence between patients with BRAFV600E-positive and -negative PTC. Patients with PTC who underwent initial thyroid surgery between January 2010 and December 2018 at Seoul St. Mary's Hospital (Seoul, Republic of Korea) were retrospectively reviewed. The BRAFV600E-positive (n = 1768) and BRAFV600E-negative groups (n = 428) were divided into two subgroups: younger (<35 years) and older groups (≥55 years). In the BRAFV600E-positive group, the younger group exhibited higher lymphatic and vascular invasion rates, more positive lymph nodes, higher lymph node ratios, and higher recurrence rates than the older group (5.9% vs. 2.1%). Multivariate analysis revealed that age, lymphatic invasion, and N category were significant risk factors in the BRAFV600E-positive group. In the BRAFV600E-positive group, the younger group had a higher recurrence risk than the older group (OR, 2.528; 95% confidence interval, 1.443-4.430; p = 0.001). In the BRAFV600E-negative group, age had no impact on recurrence risk. These results contribute to tailored treatment strategies and informed patient management.

Loss of CDH16 expression is a strong independent predictor for lymph node metastasis in Middle Eastern papillary thyroid cancer

Papillary Thyroid Cancer (PTC) is the most common type of thyroid cancer. The membrane-associated glycoprotein cadherin-16 (CDH16) plays a significant role in the embryonal development of thyroid follicles and cell adhesion. Previous studies have indicated a substantial downregulation of CDH16 in PTC. However, its role in Middle Eastern PTC has not been elucidated. We analyzed a tissue microarray comprising 1606 PTC and 240 normal thyroid tissues using immunohistochemistry to assess CDH16 expression and determine its clinico-pathological associations. We also conducted BRAF and TERT mutations analyses through Sanger sequencing. Disease-free survival (DFS) was assessed using Kaplan–Meier curves. CDH16 immunostaining was seen in 100% of normal thyroid tissues but only in 9.4% of PTC tissues (p < 0.0001). The loss of CDH16 expression was associated with aggressive PTC characteristics including bilaterality, multifocality, extrathyroidal extension, tall cell variant, lymph node metastasis (LNM) and distant metastasis. Additionally a correlation between loss of CDH16 expression and BRAF and TERT mutations was identified. Intriguingly, upon conducting multivariate logistic regression analysis, CDH16 was determined to be an independent predictor for LNM (Odds ratio = 2.46; 95% confidence interval = 1.60–3.79; p < 0.0001). Furthermore, CDH16 loss was associated with a shorter DFS (p = 0.0015). However, when we further subdivided CDH16 negative patients based on the co-existence of TERT and/or BRAF mutations, we found that patients with both CDH16 negative expression and TERT mutation exhibited the shortest DFS (p < 0.0001). In conclusion, our results suggest that CDH16 protein expression could serve as a valuable diagnostic tool for PTC. Furthermore, these findings demonstrate that the loss of CDH16 expression is an independent predictor of LNM and may contribute to the aggressiveness of PTC. Therefore, downregulation of CDH16 in PTC might be a potential target for designing novel therapeutic strategies to treat PTC.