Aggressive Papillary Thyroid Cancer Research Articles

7914 Staged Treatment with Radioiodine Following Lobectomy in a Case of High Risk Papillary Thyroid Carcinoma

Abstract Disclosure: L. Pathak: None. A. Sharma: None. K. Rao: None. M.G. Jakoby: None. Introduction: Radioiodine ([1]3[1]I ) is usually reserved for patients with differentiated thyroid carcinoma (DTC) who are at high risk of persistence or recurrence after thyroidectomy. We present a case of papillary thyroid carcinoma (PTC) with extrathyroidal extension managed by lobectomy and staged [1]3[1]I ablation of the contralateral lobe and metastases due to comorbidities that made oncologic resection prohibitive. Case Description: A 58-year-old male had a 2.2 cm focus of PTC in the left thyroid lobe that extended into extrathyroidal soft tissue, adjacent trachea, and completely compromised the left recurrent laryngeal nerve. Due to left vocal cord paralysis and subglottic tracheal stenosis, left lobectomy was performed but oncologic resection (total thyroidectomy and tracheal resection) was deferred. The patient underwent recombinant human TSH (rhTSH) stimulated treatment with 30 mCi (1.1 GBq) of [1]3[1]I for right thyroid lobe ablation followed 60 d later by 180 mCi (6.7 GBq) of [1]3[1]I to treat metastases. Response to treatment was incomplete, with unstimulated thyroglobulin level falling from 293.9 to 18.9 ng/mL 1 y after [1]3[1]I and CT of the neck notable for a 2.7 cm left thyroid bed mass with invasion of adjacent trachea and a 1.0 cm right paratracheal mass, both of which exhibited hypermetabolism on PET imaging and yielded cytology consistent with poorly differentiated thyroid carcinoma (PDTC). A cluster of left supraclavicular lymph nodes showed both hypermetabolism on PET and radioiodine uptake on rhTSH scan. This patient is being prepared for surgical resection of the left thyroid bed and right paratracheal tumors and left lateral lymph node dissection. Discussion: Radioiodine lobar ablation is an alternative to completion thyroidectomy in patients with an unexpected diagnosis of DTC after lobectomy, with a recent meta-analysis finding a success rate of 69%. No difference in thyroid cancer recurrence rates was found in nearly 500 matched pairs of patients undergoing completion thyroidectomy or radioiodine lobar ablation. Unfortunately, staged lobar ablation followed by high dose [1]3[1]I was not successful in treating this high-risk PTC patient. Cases of coexisting PTC and PDTC are reported, and [1]3[1]I treatment was unsuccessful at treating PDTC that was not apparent on postsurgical histopathology. This case indicates that surgery is preferable to staged [1]3[1]I treatment of patients with aggressive PTC, especially if there are no comorbidities that make total thyroidectomy a high-risk procedure. Presentation: 6/2/2024

The Role of Risk Factors for the Progression of Patients with T1b-T2 Papillary Thyroid Carcinoma (PC) during Long-Term Follow-Up.

Background/Objectives: Recurrence prediction for patients with PC and tumor sizes ranging between 1 and 4 cm, classified as T1b and T2, remains a controversial problem. We evaluated which risk factors, identified during the primary tumor surgery, might play a prognostic role in predicting disease progression. Methods: We retrospectively enrolled 363 patients with classic PC who were in follow-up (207 T1b, 156 T2), with tissue risk factors at surgery in 209/363 cases. In all cases, an 131I-whole-body scan, SPECT/CT, and US were employed to detect any metastases during follow-up, and histology was used to confirm lesions. In the absence of surgery, metastases were validated by radioisotopic and radiologic procedures, eventually culminating in a needle biopsy and sequential thyroglobulin changes. Results: Metastases occurred in 61/363 (16.8%) patients (24 T1b, 37 T2). In 50/61 cases, the following risk factors were identified: minimal extrathyroid tumor extension (mETE) alone in 12/50 patients, neck lymph node (LN) metastases in 8/50 cases, and multifocality/multicentricity (M/M) in 6/50 cases. In the remaining 24/50 cases, the risk factors were associated with each other. From a Cox regression multivariate analysis, metastasis development was significantly (p < 0.001) influenced by only mETE and LN metastases, with a shorter disease-free survival (log-rank test). Conclusions: The current study proves that mETE and neck LN metastases are associated with aggressive PC. While LN metastasis' role is known, mETE's role is still being debated, and was removed by the AJCC's eighth edition because it was considered to not be associated with an unfavorable prognosis. However, this interpretation is not supported by the present study and, according to comparable studies, we suggest a revision of the mETE classification be considered in the next AJCC edition.

Evaluation of epithelial-to-mesenchymal transition and Ki-67 index in aggressive papillary thyroid cancer

ObjectivesThe present study aims to characterize immunohistochemical features of markers associated with Epithelial–Mesenchymal Transition (EMT) and proliferative activity that could lead to death in Papillary Thyroid Cancer (PTC). MethodsClinical data and tumor material were retrospectively collected. The patients were separated into death from PTC (Group 1), metastatic cases with indolent behavior (Group 2) and non-metastatic indolent PTC (Group 3). Immunohistochemical assessment of E-cadherin, β-catenin, Vimentin, ZEB-1 and Ki-67 was performed in each tumor and a semiquantitative estimation of the percentage of expression was fulfilled on the best marking area at high of the tumor invasion front. Results31 patients were included, 15 that died from PTC (Group 1), 6 in Group 2 and 10 in Group 3. The proliferative marker Ki-67 showed a significant difference in its expression in the tumor invasion front between the groups, specifically between groups 1 and 3 (p = 0.006). On the other hand, EMT-related immunohistochemical markers did not show significant difference in their percentage of expression, since loss of E-cadherin, β-catenin and Vimentin was observed in most cases at the invasion front. ConclusionPatients that died from PTC had a significantly higher Ki-67 labelling index compared to patients with indolent disease (cutoff of 11%). Ki-67 may have a role as a prognostic marker and could be considered for routine use in PTC. Level of evidence4.

BRAF-induced EHF expression affects TERT in aggressive papillary thyroid cancer.

BRAFV600E and TERT promoter mutations in papillary thyroid carcinoma (PTC) have a synergistic effect on prognosis. This effect is believed to arise from MAPK activation triggered by BRAFV600E, leading to the upregulation of ETS transcription factors that bind to the mutant TERT promoter. To explore the role of ETS factors in relation to clinical features, BRAFV600E and TERT promoter mutations in PTC. Transcriptomic data for 28 ETS factors were analyzed in the PTC cohort of The Cancer Genome Atlas (TCGA, n=399) and subsequently validated in a local cohort (n=93). In vitro experiments were performed to investigate the regulatory role in relation to BRAFV600E and TERT expression. TCGA identified ETS1, ERG, FLI1, GABPA, EHF, ETV6 and SPDEF as differentially expressed genes between stages I+II and III+IV. In both cohorts, EHF was consistently associated with adverse clinical features, BRAFV600E and TERT promoter mutation/expression. Notably, in BRAFV600E mutated PTC, high EHF expression was associated with shorter disease-free survival. Cases harboring concurrent BRAFV600E, TERT promoter mutations and high EHF expression exhibited the shortest disease-free survival. In cells harboring concurrent BRAFV600E and TERT promoter mutation, over-expression of EHF significantly increased TERT expression while knockdown or pharmacological inhibition of BRAF significantly decreased both EHF and TERT expression. In addition, ChIP-qPCR analysis suggested a potential binding of EHF in TERT promoter mutant cells but not in TERT promoter wild-type cells. The ETS transcription factor EHF is associated with poor prognosis in PTC. This is potentially mediated by BRAF-induced upregulation of EHF which in turn increases TERT expression in TERT promoter mutated cells.

BRAFV600E/p-ERK/p-DRP1(Ser616) Promotes Tumor Progression and Reprogramming of Glucose Metabolism in Papillary Thyroid Cancer.

Background: Papillary thyroid cancer (PTC) with the BRAFV600E mutation is associated with a poorer prognosis. BRAF inhibitors may demonstrate limited efficacy due to emerging drug resistance. The Warburg effect may have cancer therapeutic implications. It is not known if the BRAFV600E mutation is associated with altered glucose metabolism in PTC. Methods: This study examined the effect of BRAFV600E and dynamin-related protein 1 (DRP1) on various cellular processes in PTC cells, including cell proliferation, migration, invasion, mitochondrial fission, glucose metabolism, reactive oxygen species (ROS) generation, and apoptosis. We used RT-qPCR to assess the expression of key glycolytic enzymes in thyroid cancer tissues. Additionally, the regulatory interaction between BRAFV600E and DRP1 was investigated through Western blot and immunohistochemical staining. We further evaluated the impact of DRP1 in PTC and the inhibitory effects of dabrafenib and 2-deoxy-d-glucose (2-DG) in vitro and invivo. Results: We found that the BRAFV600E mutation significantly augments aerobic glycolysis while suppressing oxidative phosphorylation in PTC. We identified the BRAFV600E/p-ERK/p-DRP1(Ser616) signaling pathway as a critical mediator in PTC progression. First, the BRAFV600E/p-ERK/p-DRP1(Ser616) signaling pathway enhances cell proliferation by upregulating hexokinase 2 expression and thereby increasing aerobic glycolysis. Second, it inhibits apoptosis by promoting mitochondrial fission and reducing ROS levels. Moreover, we demonstrated that the combination therapy of 2-DG and dabrafenib markedly impedes the progression of BRAFV600E-positive PTC. Conclusion: The BRAFV600E/p-ERK/p-DRP1(Ser616) signaling pathway plays a pivotal role in glucose metabolism reprogramming, contributing to the aggressiveness and progression of BRAFV600E-positive PTC. Our findings suggest that a combined therapeutic approach using 2-DG and dabrafenib has the potential to improve the outcome of PTC patients with BRAFV600E.

Gene Expression Profiles of AHNAK2, DCSTAMP, FN1, and TERT Correlate With Mutational Status and Recurrence in Papillary Thyroid Carcinoma.

Papillary thyroid carcinoma (PTC), the most common malignancy of follicular cell derivation, is generally associated with good prognosis. Nevertheless, it is important to identify patients with aggressive PTCs and unfavorable outcome. Molecular markers such as BRAFV600E mutation and TERT promoter mutations have been proposed for risk stratification. While TERT promoter mutations have been frequently associated with aggressive PTCs, the association of BRAFV600E mutation with increased recurrence and mortality is less clear and has been controversially discussed. The aim of the present study was to analyze whether differentially expressed genes can predict BRAFV600E mutations as well as TERT promoter mutations in PTCs. RNA sequencing identified a large number of differentially expressed genes between BRAFV600E and BRAFwildtype PTCs. Of those, AHNAK2, DCSTAMP, and FN1 could be confirmed in a larger cohort (n = 91) to be significantly upregulated in BRAFV600E mutant PTCs using quantitative RT-PCR. Moreover, individual PTC expression values of DCSTAMP and FN1 were able to predict the BRAFV600E mutation status with high sensitivity and specificity. The expression of TERT was detected in all PTCs harboring TERT promoter mutations and in 19% of PTCs without TERT promoter mutations. Tumors with both TERT expression and TERT promoter mutations were particularly associated with aggressive clinicopathological features and a shorter recurrence-free survival. Altogether, it will be interesting to explore the biological function of AHNAK2, DCSTAMP, and FN1 in PTC in more detail. The analysis of their expression patterns could allow the characterization of PTC subtypes and thus enabling a more individualized surgical and medical treatment.

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

PurposeHobnail 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.MethodsPathological 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.ResultsTwenty-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.ConclusionPTC 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.

Sonographic characteristics and clinical characteristics combined with nomogram for predicting the aggressiveness of papillary thyroid carcinoma coexisted with Hashimoto’s thyroiditis

ObjectiveThe association between Papillary Thyroid Carcinoma (PTC) and coexistent Hashimoto’s Thyroiditis (HT) was controversial. The purpose of this study was to evaluate the presence of HT exerts any influence on the aggressiveness of PTC, and to establish a nomogram for predicting the possibility of aggressiveness in PTC. Methods373 consecutive PTC patients with/without coexistent HT from January 2017 to December 2020 were retrospective reviewed. Patients’ clinicopathologic and sonographic characteristics were collected for univariate and multivariate analyses. A nomogram was established based on the risk factors for aggressiveness in PTC. ResultsMale (p = 0.001), tumor size >1.0 cm (p = 0.046) and lymph node metastasis (p = 0.018) were negatively associated with PTC coexisted with HT, while it was significantly positively associated with the frequence of multifocality (p = 0.010). Univariate and multivariate analyses suggested that age ≥55 years (p = 0.000), male (p = 0.027), HT (p = 0.017), tumor size >1.0 cm (p = 0.015), multifocality (p = 0.041), distance to capsular ≤0 cm (p = 0.050) and blood flow (Grade I: p = 0.044) were independent risk factors for predicting the aggressiveness in PTC. A nomogram according to these predictors was further developed and validated. The receiver operating characteristic curve (AUC = 0.734 and 0.809 for training and validation cohorts, respectively) and decision curve analyses indicated that the nomogram model was clinically useful. The calibration curve revealed that the nomogram exhibited an excellent consistency. ConclusionsIn this study, the coexistent HT might play a protective role in preventing the proliferation of PTC. Dispensable aggressive treatment may be reduced in PTC by pre-operative identification of sonographic and clinical characteristics and incorporating with the predicted nomogram model.

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. 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.