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Utilities of RAS mutations in pre-operative fine needle biopsies for decision-making for thyroid nodule management: results from a single-center prospective cohort.
术前细针活检中 RAS 突变的效用用于甲状腺结节管理的决策: 来自单中心前瞻性队列的结果。
- 影响因子:6.69
- DOI:10.1089/thy.2019.0116
- 作者列表:"Guan H","Toraldo G","Cerda SR","Godley FA","Rao SR","McAneny D","Doherty GM","Braverman LE","Lee SL
- 发表时间:2020-01-29
Abstract
BACKGROUND:It has been advocated to apply individualized strategies to evaluate thyroid nodules due to the growing awareness that the pathogenesis of thyroid cancer is not uniform. Molecular markers in fine needle biopsies (FNBs) may be helpful for the diagnosis and management decisions. Unlike the detection of BRAF mutations, the clinical utility of RAS mutations has not been fully elucidated. This study aimed to present a real world performance of RAS mutations in identifying thyroid malignancies, to investigate the nature of thyroid tumors carrying RAS mutations, and to provide an additional reference for interpreting how to utilize the presence of RAS mutations in the decision making process of thyroid nodule management. METHODS:Between February 2015 and December 2017, 1400 sequential thyroid biopsies were performed at Boston Medical Center. Of these, 546 FNBs were evaluated for RAS mutations using a ThyroSeq next-generation sequencing panel. Nodules carrying RAS mutations were prospectively followed and medical records were collected. RESULTS:ThyroSeq successfully provided molecular information in 504 nodules; 173 with molecular alteration(s); 80 positive for mutations in the K-, N-, or H- RAS genes. RAS gene mutations constituted up to 46.2% of the total molecular alterations found in the study. Fifty-six of the 80 RAS-positive nodules underwent surgery, 33 (58.9%) were confirmed to be benign, 7 (12.5%) were non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), and 16 (28.6%) were thyroid carcinomas. The positive predictive value (PPV), negative predictive value (NPV) and accuracy of RAS mutations for identifying malignancies among cytologically indeterminate nodules were 25.5%, 89.7% and 54.0% when NIFTP was not counted as cancer. A combination of RAS and other mutations increased the risk of malignancy. Twelve histopathologically proved RAS-only-positive malignant nodules all showed low-risk features and favorable prognosis. RAS isoforms added little assistance for predicting a malignancy and the response to therapy in our series. CONCLUSIONS:RAS mutations represent the most frequently detected genetic alterations in our series. RAS mutations, when occurring alone, are not helpful markers to identify malignancy among Bethesda III/IV cytologies, but may predict favorable behavior, and hence should be considered to guide initial management.
摘要
背景: 由于人们越来越认识到甲状腺癌的发病机制并不统一,因此一直主张应用个体化策略来评估甲状腺结节。细针活检 (FNBs) 中的分子标志物可能有助于诊断和治疗决策。与 BRAF 突变的检测不同,RAS 突变的临床效用尚未完全阐明。本研究旨在展示 RAS 突变在识别甲状腺恶性肿瘤中的真实表现,研究携带 RAS 突变的甲状腺肿瘤的性质, 并为解释如何在甲状腺结节管理的决策过程中利用 RAS 突变的存在提供额外的参考。 方法: 2015年2月至 2017年12月间,波士顿医疗中心进行了 1400 例甲状腺活检。其中,使用甲状腺 seq 下一代测序 panel 评估了 546 个 FNBs 的 RAS 突变。前瞻性随访携带 RAS 突变的结节并收集病历。 结果: ThyroSeq 成功提供了 504 个结节的分子信息; 173 个出现分子改变; 80 个 K 、 N 或 H-RAS 基因突变阳性。RAS 基因突变占研究中发现的总分子改变的 46.2%。80 个 RAS 阳性结节中 56 个接受了手术,33 个 (58.9%) 证实为良性,7 个 (12.5%) 均为具有乳头状核样特征 (NIFTP) 的非侵袭性滤泡状甲状腺肿瘤,16 例 (28.6%) 为甲状腺癌。当 NIFTP 不计入癌症时,RAS 突变识别细胞学不确定结节中恶性肿瘤的阳性预测值 (PPV) 、阴性预测值 (NPV) 和准确性分别为 25.5% 、 89.7% 和 54.0%。RAS 和其他突变的组合增加了恶性肿瘤的风险。12 个病理证实为 RAS 阳性的恶性结节均表现为低危特征,预后良好。在我们的系列中,RAS 亚型对预测恶性肿瘤和治疗反应几乎没有帮助。 结论: RAS 突变代表了我们系列中最常检测到的遗传改变。RAS 突变,单独发生时,不是 Bethesda III/IV 细胞中鉴别恶性肿瘤的有用标志物,但可能预测有利的行为,因此应考虑指导初始管理。
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METHODS:OBJECTIVES:To assess the prevalence of Hashimoto thyroiditis (HT) in primary thyroid lymphoma (PTL) and whether it differs between mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL). METHODS:Electronic databases were searched for studies assessing HT prevalence in PTL, based on antithyroid antibodies, clinical history, or pathology. Pooled prevalence of HT and its association with histotype (MALT or DLBCL) were calculated. RESULTS:Thirty-eight studies with 1,346 PTLs were included. Pooled prevalence results were 78.9% (any HT evidence), 65.3% (antithyroid antibodies), 41.7% (clinical history), and 64% (pathology). HT prevalence was significantly higher in MALT lymphoma than in DLBCL (P = .007) and in mixed DLBCL/MALT than in pure DLBCL (P = .002). CONCLUSIONS:Overall, 78.9% of patients with PTL have any HT evidence, but only half of these had been clinically followed. The difference in HT prevalence suggests that a subset of DLBCL may not derive from MALT lymphoma.
METHODS:Background Whether chronic lymphocytic thyroiditis (CLT) influences the risk of development and the progression of papillary thyroid cancer (PTC) remains uncertain. We investigated the effects of CLT on the clinicopathologic features and prognosis of PTC. Methods Two thousand nine hundred twenty-eight consecutive patients with PTC treated between 2009 and 2017 were divided into two groups: one with chronic lymphocytic thyroiditis and one without; 1174 (40%) of the patients had coincident CLT. Results In univariate analysis, CLT correlated positively with small tumor size, frequent extrathyroidal extension, multifocal diseases, and p53 but negatively with central lymph node (LN) metastasis and BRAF mutation. In multivariate analysis, CLT was associated with extrathyroidal extension and multifocal disease; however, it was not a prognostic factor for recurrence even though it was associated with two aggressive factors. Compared with patients with PTC alone, there were more retrieved central LNs in the PTC + CLT group, and these patients also underwent more invasive diagnostic tests such as fine needle aspiration cytology and frozen biopsy of LN. Conclusions The CLT patients with PTC had better behavior features and prognoses than did those with PTC alone despite frequent multifocality and extrathyroidal extension. However, precaution may be necessary to avoid performing invasive diagnostic procedures for lateral LN metastasis and to manage the patients appropriately.
METHODS::PTPN2 is one of the members of the protein Tyrosine Phosphatases (PTPs) family. To explore the promotive effect of upregulated PTPN2 induced by inflammatory response or oxidative stress on the progression of thyroid cancer. PTPN2 level in thyroid cancer tissues and cell lines was detected. Kaplan-Meier method was applied for evaluating the prognostic value of PTPN2 in thyroid cancer patients. After stimulation of inflammatory response (treatment of IFN-γ and TNF-α), or oxidative stress (treatment of H2O2), protein level of PTPN2 in K1 cells was measured by Western blot. Regulatory effects of PTPN2 on EdU-positive staining and Ki-67 positive cell ratio in K1 cells either with H2O2 stimulation or not were determined. PTPN2 was upregulated in thyroid cancer tissues and cell lines. Its level was higher in metastatic thyroid cancer patients than those of non-metastatic ones. High level of PTPN2 predicted worse prognosis of thyroid cancer. Treatment of either IFN-γ or TNF-α upregulated protein level of PTPN2 in K1 cells. Meanwhile, H2O2 stimulation upregulated PTPN2, which was reversed by NAC administration. With the stimulation of increased doses of H2O2, EdU-positive staining and Ki-67 positive cell ratio were dose-dependently elevated. Silence of PTPN2 attenuated proliferative ability and Ki-67 expression in K1 cells either with H2O2 stimulation or not. Inflammatory response or oxidative stress induces upregulation of PTPN2, thus promoting the progression of thyroid cancer.