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      Diagnostic Efficacy of Ultrasound, Cytology, and BRAF V600E Mutation Analysis and Their Combined Use in Thyroid Nodule Screening for Papillary Thyroid Microcarcinoma

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          Abstract

          Background

          Ultrasound, cytology, and BRAF V600E mutation analysis were applied as valuable tools in the differential diagnosis of thyroid nodules. The aim of the present study was to evaluate the diagnostic efficiency of the three methods and their combined use in screening for papillary thyroid microcarcinoma (PTMC).

          Methods

          A total of 1,081 patients with 1,157 thyroid nodules (0.5–1 cm in maximum diameter) classified as thyroid imaging reporting and data system (TIRADS) 4–5 were recruited. All patients underwent ultrasound, fine-needle aspiration (FNA) examination, and an additional BRAF V600E mutation test. TIRADS and Bethesda System for Reporting Thyroid Cytopathology (BSRTC) were adopted to judge the ultrasound and cytological results. The receiver operating characteristic (ROC) curve was established to assess the diagnostic values of different methods.

          Results

          Of the 1,157 nodules, 587 were benign and 570 were PTMCs. BRAF V600E mutation test had highest sensitivity (85.4%), specificity (97.1%), accuracy (91.4%), and area under the ROC curve (Az) value (0.913) among the three methods. The combination of BSRTC and BRAF V600E mutation analysis yielded a considerably high sensitivity (96.0%), accuracy (94.3%), and negative predictive value (95.9%) than either BSRTC or BRAF V600E mutation alone ( P < 0.0001 for all comparisons). Of all the methods, the combined use of the three methods produced the best diagnostic performance (Az = 0.967), which was significantly higher than that (Az = 0.943) for the combination of BSRTC and BRAF V600E mutation ( P < 0.0001). The diagnostic accuracy of the molecular method in the 121 nodules with indeterminate cytology was 90.1% (109/121), which was significantly higher than that of TIRADS classification, 74.4% (90/121) ( P = 0.002).

          Conclusion

          The combined use of ultrasound, cytology, and BRAF V600E mutation analysis is the most efficient and objective method for diagnosing PTMC. Both BRAF V600E mutation and TIRADS classification are potentially useful adjuncts to differentiate thyroid nodules, especially indeterminate samples classified as BSRTC III.

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          Most cited references40

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          The 2017 Bethesda System for Reporting Thyroid Cytopathology.

          The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) established a standardized, category-based reporting system for thyroid fine-needle aspiration (FNA) specimens. The 2017 revision reaffirms that every thyroid FNA report should begin with one of six diagnostic categories, the names of which remain unchanged since they were first introduced: (i) nondiagnostic or unsatisfactory; (ii) benign; (iii) atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS); (iv) follicular neoplasm or suspicious for a follicular neoplasm; (v) suspicious for malignancy; and (vi) malignant. There is a choice of two different names for some of the categories. A laboratory should choose the one it prefers and use it exclusively for that category. Synonymous terms (e.g., AUS and FLUS) should not be used to denote two distinct interpretations. Each category has an implied cancer risk that ranges from 0% to 3% for the "benign" category to virtually 100% for the "malignant" category, and, in the 2017 revision, the malignancy risks have been updated based on new (post 2010) data. As a function of their risk associations, each category is linked to updated, evidence-based clinical management recommendations. The recent reclassification of some thyroid neoplasms as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has implications for the risk of malignancy, and this is accounted for with regard to diagnostic criteria and optional notes. Such notes can be useful in helping guide surgical management.
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            The Bethesda System for Reporting Thyroid Cytopathology: a meta-analysis.

            We aimed to investigate the validity of the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) through meta-analysis. All publications between January 1, 2008 and September 1, 2011 that studied TBSRTC and had available histological follow-up data were retrieved. To calculate the sensitivity, specificity and diagnostic accuracy, the cases diagnosed as follicular neoplasm, suspicious for malignancy and malignant which were histopathologically confirmed as malignant were defined as true-positive. True-negative included benign cases confirmed as benign on histopathology. The nondiagnostic category was excluded from the statistical calculation. The correlations between the 6 diagnostic categories were investigated. The publications review resulted in a case cohort of 25,445 thyroid fine-needle aspirations, 6,362 (25%) of which underwent surgical excision; this group constituted the basis of the study. The sensitivity, specificity and diagnostic accuracy were 97, 50.7 and 68.8%, respectively. The positive predictive value and negative predictive value were 55.9 and 96.3%, respectively. The rates of false negatives and false positives were low: 3 and 0.5%, respectively. The results of meta-analysis showed high overall accuracy, indicating that TBSRTC represents a reliable and valid reporting system for thyroid cytology. Copyright © 2012 S. Karger AG, Basel.
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              Thyroid imaging reporting and data system for US features of nodules: a step in establishing better stratification of cancer risk.

              To develop a practical thyroid imaging reporting and data system (TIRADS) with which to categorize thyroid nodules and stratify their malignant risk. The institutional review board approved this retrospective study, and the requirement to obtain informed consent for the review of images and records was waived. From May to December 2008, ultrasonographically (US)-guided fine-needle aspiration biopsy (FNAB) was performed in 3674 focal thyroid nodules in 3414 consecutive patients. The study included the 1658 thyroid nodules (≥1 cm in maximum diameter at US) in 1638 patients (1373 women, 265 men) for which pathologic diagnosis or follow-up findings were available. Univariate and multivariate analyses with generalized estimating equations were performed to investigate the relationship between suspicious US features and thyroid cancer. A score for each significant factor was assigned and multiplied by the β coefficient obtained for each significant factor from multivariate logistic regression analysis. Scores for each significant factor were then added, resulting in an equation that fitted the probability of malignancy in thyroid nodules. The authors evaluated the fitted probability by using a regression equation; the risk of malignancy was determined according to the number of suspicious US features. The following US features showed a significant association with malignancy: solid component, hypoechogenicity, marked hypoechogenicity, microlobulated or irregular margins, microcalcifications, and taller-than-wide shape. As the number of suspicious US features increased, the fitted probability and risk of malignancy also increased. Positive predictive values according to the number of suspicious US features were significantly different (P < .001). Risk stratification of thyroid malignancy by using the number of suspicious US features allows for a practical and convenient TIRADS.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                03 January 2022
                2021
                : 11
                : 746776
                Affiliations
                [1] 1 Department of Ultrasound, Renji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, China
                [2] 2 Department of Laboratory Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, China
                [3] 3 Department of Head and Neck Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, China
                Author notes

                Edited by: Avraham Eisbruch, University of Michigan, United States

                Reviewed by: Ludovico Docimo, University of Campania Luigi Vanvitelli, Italy; Zubair Wahid Baloch, University of Pennsylvania, United States

                *Correspondence: Fenghua Li, fenghua-li@ 123456163.com

                †These authors have contributed equally to this work

                This article was submitted to Head and Neck Cancer, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2021.746776
                8761628
                35047385
                25b5d004-a828-46af-a9f2-be778456d024
                Copyright © 2022 Du, Han, Chen, Ma, Shen, Chen and Li

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 24 July 2021
                : 22 October 2021
                Page count
                Figures: 3, Tables: 6, Equations: 0, References: 40, Pages: 11, Words: 6566
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                thyroid nodule,papillary thyroid microcarcinoma,ultrasound,fine-needle aspiration,brafv600e mutation

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