Clinicopathological Features Of Papillary Thyroid Carcinoma Research Articles

Analysis of the factors associated with clinicopathological characteristics of papillary thyroid carcinoma

Objective BRAFV600E mutation, RET/PTC rearrangement, and the concomitant of Hashimoto's thyroiditis(HT)could influence clinicopathological features of papillary thyroid carcinoma(PTC). This study is to investigate the distribution of three factors in PTC and to analyze their associations with clinicopathological characteristics. Methods Fine-needle aspiration samples were collected in a total of 122 conventional PTC patients, who were confirmed by surgery. The clinicopathological features were collected to analyze its association with different factors. BRAFV600E mutation and RET/PTC rearrangement were detected by pyrosequencing and Taqman-qPCR, respectively. Results BRAFV600E mutation was significantly correlated with an older age and a less coexistence with HT(P<0.05). In contrast, RET/PTC rearrangement was more prevalent in young patients and was associated with the concomitant of HT(P<0.05). In the age of ≥20 year and<45 year groups, BRAFV600E mutation was significantly associated with extrathyroidal invasiveness. RET/PTC rearrangement was significantly associated with bilateral lymph node metastasis and the number of metastatic lymph node. Conclusions The distribution of three factors were different in PTC patients. In addition to the age at diagnosis, all of three factors should also be considered together to analyze the association of clinicopathological features of PTC. (Chin J Endocrinol Metab, 2015, 31: 941-945) Key words: BRAFV600E mutation; RET/PTC rearrangement; Hashimoto's disease; Papillary thyroid carcinoma

Associations of the BRAF (V600E) mutation and p53 protein expression with clinicopathological features of papillary thyroid carcinomas patients.

The BRAF (V600E) mutation is the most prevalent type of genetic alteration that has been identified in papillary thyroid carcinoma (PTC); in addition, previous immunohistochemical studies have revealed the overexpression of p53 protein in PTC. The aim of the present study was to investigate the prevalence of the BRAF (V600E) mutation and the expression of p53 in PTC, as well as to determine any associations between these two factors and the clinicopathological features of PTC. The study was performed on 66 PTC patients who underwent surgical tumor resection between January and December 2012. Polymerase chain reaction-based DNA amplification was used to analyze extracted DNA from the tumor specimens in order to determine the prevalence of the BRAF (V600E) mutation. In addition, immunohistochemical analysis was employed in order to evaluate the protein expression of p53 in sections of tumor tissue. Furthermore, statistical analysis was performed in order to determine any associations among the BRAF (V600E) mutation prevalence, p53 overexpression and the clinicopathological features of PTC patients, including age, gender, tumor size, multiplicity, lymph node metastasis and extrathyroidal extension. The results revealed that the BRAF (V600E) mutation was observed in 50 (75.8%) of the 66 PTC patients and overexpression of p53 was found in 52 (78.8%) of 66 cases. No significant correlations were observed between the BRAF (V600E) mutation or p53 protein overexpression and the clinicopathological features of patients. However, the BRAF (V600E) mutation demonstrated noteworthy, but non-significant, correlations with the overexpression of p53 (P=0.0854) and extrathyroidal extension (P=0.0661). In addition, a significant correlation was observed between lymph node metastasis and bilaterality (P=0.0280). In conclusion, the present study demonstrated that the BRAF (V600E) mutation and overexpression of p53 were not significantly correlated with clinicopathological features of PTC, although notable associations were identified between BRAF (V600E) mutation and overexpression of p53 as well as extrathyroidal extension. In addition, lymph node metastasis was significantly associated with bilaterality.

Clinical significance of BRAF V600E mutation in 154 patients with thyroid nodules.

The aim of the present study was to investigate the prevalence of the BRAF V600E mutation in papillary thyroid carcinoma (PTC) patients from eastern coastal China and to determine whether it is correlated with the clinicopathological features of PTCs with or without current Hashimoto thyroiditis (HT). The BRAF V600E mutation status was analyzed in 206 thyroid nodules of 154 patients undergoing thyroidectomy using polymerase chain reaction and bi-directional sequencing. Multivariate analysis was performed to investigate the association of the BRAF V600E mutation with clinicopathological features. Thyroid nodules were classified as PTC, nodular goiter (NG), adenomatoid nodule, adenoma and HT. The BRAF V600E mutation was observed in 61.5% of PTCs analyzed; it was also detected in one normal tissue adjacent to PTC and one NG. One patient exhibited double mutations in the BRAF gene; the BRAF V600E mutation in the PTC lesion and the BRAF K601E mutation in the contralateral NG lesion. Patients harboring the BRAF V600E mutation had higher thyroid stimulating hormone levels (2.453±1.464 vs. 1.966±1.296 mIU/l), a reduced occurrence of papillary thyroid microcarcinoma (55.0 vs. 88%), and a higher occurrence of lymph node metastasis (LNM; 42.5 vs. 16.0%) compared with those with wild-type BRAF (all P<0.05). Binary logistic regression analysis revealed that the BRAF V600E mutation was associated with LNM of PTC (hazard ratio, 5.051; 95% confidence interval, 1.068-23.893; P=0.041). Conversely, no association was identified between the BRAF V600E mutation and HT (38.5 vs. 67.3%, χ2=3.656, P=0.056). Thus, in regional PTCs, the BRAF V600E mutation was prevalent, suggesting that it may be an early and phenotypically defining molecular event in PTC, and may represent an independent factor that predicts LNM.

Strong Expression of HBME-1 Associates with High-Risk Clinicopathological Factors of Papillary Thyroid Carcinoma

Thyroid cancer comprises a heterogeneous group of lesions with great diversity of biological behaviour. Markers which could help clinicians to identify high-risk patients for tailored optimization of clinical management are of crucial importance. HBME-1 protein level was analysed immunohistochemically using routinely prepared archival tissue sections of a broad range of papillary thyroid carcinoma (PTC) variants and in corresponding lymph node metastases (LNM). The results were evaluated in comparison with clinicopathological features of PTC. Positive immunoreaction was noticed in most classical (83/92; 90.2 %), follicular (60/71; 84.5 %) and trabecular (4/5; 80.0 %) variants of PTC. All cases of macrofollicular, Warthin-like and diffuse sclerosing PTC variants were HBME-1 positive (4/4, 3/3, 2/2; 100 % respectively). Tall cell and solid PTC variants showed diversity of staining (2/3; 66.67 % and 13/23; 56.52 % respectively), while PTCs with mixed histological pattern containing insular areas were mainly weakly positive (2/5; 40.0 %). A single case of clear cell PTC variant showed no reaction. Moreover, all matched metastatic PTC into lymph nodes (LNM) were HBME-1 positive (17/17; 100 %) and expressed HBME-1 in a similar pattern to the matched primary tumour. We also found a statistically significant association between high HBME-1 expression and the presence of lymph node metastasis, advanced pT status and pTNM stage (P < 0.05), but only a tendency for association with extrathyroidal invasion of the tumour (P = 0.058). Therefore, we recommend using immunoexpression of HBME-1 as useful mean to increase the likelihood of detecting most PTC variants and to predict some unfavourable clinical parameters in these patients.

Low VHL mRNA expression is associated with more aggressive tumor features of papillary thyroid carcinoma.

Alterations of the von Hippel–Lindau (VHL) tumor suppressor gene can cause different hereditary tumors associated with VHL syndrome, but the potential role of the VHL gene in papillary thyroid carcinoma (PTC) has not been characterized. This study set out to investigate the relationship of VHL expression level with clinicopathological features of PTC in an ethnically and geographically homogenous group of 264 patients from Serbia, for the first time. Multivariate logistic regression analysis showed a strong correlation between low level of VHL expression and advanced clinical stage (OR = 5.78, 95% CI 3.17–10.53, P<0.0001), classical papillary morphology of the tumor (OR = 2.92, 95% CI 1.33–6.44, P = 0.008) and multifocality (OR = 1.96, 95% CI 1.06–3.62, P = 0.031). In disease-free survival analysis, low VHL expression had marginal significance (P = 0.0502 by the log-rank test) but did not appear to be an independent predictor of the risk for chance of faster recurrence in a proportion hazards model. No somatic mutations or evidence of VHL downregulation via promoter hypermethylation in PTC were found. The results indicate that the decrease of VHL expression associates with tumor progression but the mechanism of downregulation remains to be elucidated.

Suppressed Krüppel‑like factor 17 expression induces tumor proliferation, metastasis and a poor prognosis in papillary thyroid carcinoma.

Although the role of krüppel‑like factor 17 (KLF17) in the regulation of proliferation and epithelial‑mesenchymal transition has been examined in breast and liver cancer, their effect on papillary thyroid carcinoma (PTC) remains to be elucidated. The present study aimed to investigate the expression pattern of KLF17 in PTC and the correlation between KLF17 expression and the malignant potential of PTC. KLF17 expression in PTC and adjacent liver tissues was studied by polymerase chain reaction and western blot analysis, and the association between KLF17 expression and the clinicopathological features of PTC was studied in 50 patients. By using RNA interference against KLF17, the correlation between KLF17 expression and malignant potential was examined by downregulating KLF17 expression in TPC‑1 cells, and the effects of KLF17 downregulation on cell proliferation and motility were analyzed. Furthermore, the association between KLF17 expression and the surgical outcomes of PTC patients were analyzed. Downregulated expression of KLF17 was associated with a shorter overall survival time in clinical patients (P<0.05). Low KLF17 expression was significantly associated with tumor stage, tumor size, nodal stage and metastasis stage in PTC (P<0.05). The reduced expression of KLF17 promoted the motility and proliferation ability of TPC‑1 cells by altering the expression of tight junction protein 1 and Snai1, and activating the AKT pathway by upregulating inhibitor of DNA binding 1. In conclusion, the present study demonstrated that KLF17 is important in tumor proliferation and may be a useful prognostic indicator in directing therapy. Therefore, further investigation regarding the role of KLF17 in PTC is required.

BRAFT1799A mutation in the primary tumor as a marker of risk, recurrence, or persistence of papillary thyroid carcinoma

Background and objectiveThe BRAFT1799A mutation is reported to be associated with aggressive, persistent, and recurrent tumor in patients with papillary thyroid carcinoma (PTC). The association of the BRAFT1799A mutation in the primary tumor with the clinicopathological characteristics of PTC was analyzed. Patients, materials, and methodsNinety-seven PTC patients were followed up for a median of 64.1 months. The BRAFT1799A mutation was analyzed in DNA from initial thyroidectomy biopsies by PCR amplification and restriction fragment length polymorphism using the TspRI enzyme. Positive results were confirmed by DNA sequencing. The statistical association of the BRAFT1799A mutation and clinicopathological characteristics was analyzed using the relevant hypothesis tests and logistic regression. ResultsThe BRAFT1799A mutation was found in 46.4% of patients. Bivariate and multivariate analyses showed the mutation to be only associated with age over 60 years (odds ratio [OR]=5.5; 95% confidence interval [CI], 1.4–21.9; p=0.019) and to a tumor size of 1cm or greater (OR=3.6, 95% CI, 1.2–10.3; p=0.016). The mutation was not associated with histological subtype, metastasis, recurrence, more aggressive treatments (131I ablation therapy or other surgery), or PTC persistence at the end of follow-up. ConclusionsThe BRAFT1799A mutation is associated with age over 60 and a tumor size of 1cm or greater, but not with other clinicopathological characteristics, tumor recurrence, or PTC persistence.

BRAF analysis by fine needle aspiration biopsy of thyroid nodules improves preoperative identification of papillary thyroid carcinoma and represents a prognostic factor. A mono-institutional experience

The current preoperative diagnosis of a thyroid mass relies on microscopic evaluation of thyroid cells obtained by fine needle aspiration biopsy (FNAB). More recently, FNAB has been combined with molecular analysis to increase the accuracy of the cytological evaluation. In this mono-institutional prospective study, we evaluated whether the routine introduction of BRAF testing in thyroid FNAB could help ameliorate the preoperative recognition of papillary thyroid carcinoma (PTC) in "suspended" or malignant cytological categories. Moreover, we investigated the prognostic role of the BRAFV600E mutation in PTC. BRAFV600E analysis was performed in thyroid FNAB from 270 patients classified into one of five cytological categories THY1, THY2, THY3, THY4, THY5. All subsequently underwent thyroidectomy±node dissection, from October 2008 to September 2009 in our Department. For each cytological category, we considered the definitive histological diagnosis of PTC and the presence of the BRAFV600E mutation. In 141 patients with a final tissue diagnosis of PTC, we correlated the presence of BRAFV600E with gender, age, histotype, TNM, size of the lesion, extracapsular extension, node metastases and multifocality. The prevalence of the BRAFV600E mutation, among PTCs at final tissue diagnosis, was 69%. It improved the FNAB diagnostic accuracy from 88% to 91%. The BRAFV600E mutation was correlated with older age, classical variant of PTC, advanced stages in patients > 45 years. BRAFV600E testing could play a role in improving the diagnostic accuracy of FNAB for PTC, representing a useful adjuvant tool in presurgical characterization of thyroid nodes in particular cases. There is an association between the BRAFV600E mutation and some clinico-pathological characteristics of PTC.

MiR-146b is Highly Expressed in Adult Papillary Thyroid Carcinomas with High Risk Features Including Extrathyroidal Invasion and the BRAFV600E Mutation

Papillary thyroid carcinoma (PTC) are clinicopathogenetically heterogeneous. Micro-RNAs (miRNAs) are involved in the pathogenesis of diverse human cancers, including PTC. Information regarding associations between clinicopathological features of PTC with the expression of specific miRNAs, however, is sparse. In this study, we compared expression of deregulated miRNAs in PTCs to assess this was associated with selected clinicopathogenetic features. We analyzed the expression levels of three reported deregulated miRNAs (miR-221, miR-222, and miR-146b) using quantitative real-time polymerase chain reaction in 100 cases of PTCs with distinct clinicopathogenetic characteristics and 16 paired normal controls. The tumor samples were categorized into low- and high-risk groups on the basis of the tumor-node-metastasis staging system. The expression levels of miR-221, miR-222, and miR-146b were significantly associated with extrathyroidal invasion (p = 0.013, 0.05, and 0.003, respectively). The expression levels of miR-221 and miR-146b were significantly higher in the high-risk PTC group (p = 0.01 and 0.042, respectively). The miR-146b expression levels in PTCs with BRAF mutation were significantly higher than those without this mutation (p < 0.0001). There were no other associations between the expression of these miRNAs and other clinicopathological parameters. Our results show the potential importance of miR-221, miR-222, and miR-146b in determining the aggressive properties of PTCs and highlight the need to identify the gene targets of these miRNAs.

BRAFV599E mutation and RET/PTC rearrangements in papillary thyroid carcinoma

To detect the BRAF(V599E) mutation and the RET/PTC chimeric gene in benign and malignant thyroid diseases and to explore their correlation with the clinicopathologic features of papillary thyroid carcinoma (PTC). PCR and RT-PCR were employed to detect BRAF(V599E) mutation and RET/PTC chimeric genes in 95 frozen and parraffine-embeded thyroid tissue. (1) BRAF(V599E) mutation was detected only in PTC (56%, 37/66) and had a high prevalence in both classic and tall cell types (70%, 29/41 and 2/3). However, follicular types of PTC and other benign and malignant thyroid diseases were negative for BRAF(V599E) mutation. (2) Fourteen (21.2%) PTC cases expressed RET/PTC chimeric gene. Among them, 5 cases (7.6%) were RET/PTC1 and 9 cases (13.6%) were RET/PTC3 respectively. (3) Statistic data did not show any correlation between the BRAF(V599E) mutation, RET/PTC and clinicopathologic features of PTC (P > 0.05). There was no overlap between BRAF(V599E) mutation and RET/PTC rearrangements. (1) BRAF(V599E) mutation and RET/PTC rearrangements were unique to PTC. The high prevalence of BRAF(V599E) mutation indicates that it is an important molecular hallmark of PTC. (2) BRAF(V599E) mutation rate was high in classic type PTC and tall cell type inferred that BRAF(V599E) mutation played an important role in their etiopathogenesis. (3) There was no overlap between BRAF(V599E) mutation and RET/PTC rearrangements suggest that they are alternative events in PTC.