Thyroid nodules are extremely common and are observed

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1 Systematic Review Contrast-Enhanced Ultrasound for Differentiation of Benign and Malignant Thyroid Lesions: Meta-analysis Otolaryngology Head and Neck Surgery 2014, Vol. 151(6) Ó American Academy of Otolaryngology Head and Neck Surgery Foundation 2014 Reprints and permission: sagepub.com/journalspermissions.nav DOI: / Dongmei Yu, MD 1, Yuna Han, MD 1, and Taotao Chen 1 No sponsorships or competing interests have been disclosed for this article. Abstract Objective. Contrast-enhanced ultrasound (CEUS) is a new noninvasive modality for the diagnosis of thyroid nodules. However, the performance of CEUS in differentiating malignant and benign thyroid nodules has not been systematically evaluated. This meta-analysis was performed to assess the accuracy of CEUS in diagnosing thyroid nodules. Data Sources. PubMed, Embase, and the references of included studies were examined. Review Methods. We recorded the characteristics of the included studies and assessed the quality of each study using the Quality Assessment of Diagnostic Accuracy Studies tool. The pooled sensitivity, specificity, positive likelihood ratio (LR), negative LR, diagnostic odds ratio (DOR), and area under the curve (AUC) were calculated. We also evaluated the publication bias. Results. This meta-analysis included 7 studies with a total of 597 thyroid nodules. The pooled the sensitivity, specificity, and positive and negative LR were 0.853, 0.876, 5.822, and 0.195, respectively. The DOR and AUC were and , respectively. Heterogeneity existed between the included studies. The results of subgroup analyses indicated that the evaluation processes are likely the predominant source of heterogeneity. No significant publication bias was observed. Conclusion. Contrast-enhanced ultrasound is a promising noninvasive technique for the differential diagnosis of benign and malignant thyroid nodules and could be a valuable supplemental method to fine-needle aspiration. Keywords contrast-enhanced ultrasound, thyroid neoplasms, diagnostic performance, meta-analysis Received April 27, 2014; revised September 8, 2014; accepted September 26, Thyroid nodules are extremely common and are observed in 50% of autopsy specimens. Approximately 5% to 15% of these are malignant. 1 Fine-needle aspiration is widely used for the diagnosis of thyroid nodules and has a relatively high sensitivity (72%-100%) and specificity (65%-98%). 2 However, there are still nondiagnostic lesions (thy1) and intermediate lesions (thy3). According to the British Thyroid Guidelines, 3 Thy1 includes samples reflecting poor operator or preparation technique or with poorly preserved cells. Thy3 includes samples with atypical features that are insufficient to assign the nodule into any category as well as follicular neoplasms. Conventional ultrasound is the preferred modality for detection of thyroid nodules. Ultrasound shows malignancy characteristics such as longer versus wider shape, irregular margin, marked hypoechogenicity, microcalcification, and increased central vascularity. 4 However, these features overlap between benign and malignant lesions, and the sensitivity and specificity of each feature is low, ranging from 10% to 74% and 40% to 96%, respectively. 5,6 Contrast-enhanced ultrasound (CEUS) is a relatively new modality that provides macro- and micro-visualization and records blood perfusion of the thyroid nodules. Using a contrast agent, CEUS can result in better vasculature representation of the thyroid gland compared with color Doppler ultrasound. However, in previous published studies, its diagnostic performance varied: sensitivity ranged from 68% to 100% and specificity ranged from 67% to 94% Currently, there are no meta-analyses that evaluate the diagnostic performance of CEUS for thyroid nodules. The purpose of this meta-analysis was to assess the overall diagnostic value of CEUS in the diagnosis of thyroid nodules. Date Sources and Review Methods Search Strategy and Selection Criteria PubMed and Embase were searched through April 2014 using the terms contrast enhanced ultrasound or contrast enhanced ultrasonography or CEUS for the diagnostic 1 Department of Special Examinations, Qingdao Women and Children Hospital, Qingdao, China Corresponding Author: Dongmei Yu, Department of Special Examinations, Qingdao Women and Children Hospital, Liaoyang West Road No 217, Shibei District, Qingdao, Shandong Province, , China. yudongmei2meiqiu@126.com

2 910 Otolaryngology Head and Neck Surgery 151(6) test****#and the terms thyroid neoplasms [Mesh] or thyroid cancer or thyroid nodules for the clinical domain. In addition, the references of identified studies were manually checked to search for other potentially eligible studies. We limited the publication language to English. We used the following inclusion criteria: (1) prospective studies that assessed the performance of CEUS for the differentiation of benign and malignant thyroid nodules, (2) study population greater than 15 patients and use of appropriate histopathological reference standards (surgical pathology or biopsy), and (3) providing data available to construct a contingency table for true-positive (TP), false-positive (FP), falsenegative (FN), and true-negative (TN) determination. Studies were excluded if they met the following criteria: (1) did not evaluate human thyroid nodules, (2) incomplete data available, (3) were duplicated or updated, and (4) the publications were reviews, editorials, corresponding letters, and case reports. Data Extraction and Quality Assessment Two investigators (D.M.Y. and Y.N.H.) independently extracted the following information from each study: author; year of publication, study country, age of patients, number of lesions, type of contrast agent, the evaluation technique of CEUS, and TP, TN, FP, and FN values. Disagreements were resolved through discussion and consensus. Quality assessments were conducted using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. 14 There were 14 items included in the QUADAS tool, and each item was rated yes (scored 1), no (scored 1), or unclear (scored 0). Studies with a score 11 were regarded as good-quality methodological studies. Statistical Analyses The heterogeneity of the included studies was estimated using the inconsistency index (I 2 ) and Cochrane Q-tests (x 2 ). When I 2 50% or P \.10, there exists substantial heterogeneity, and a random effect method should be used to pool the included studies. 15 The threshold effect was tested using the summary receiver operating characteristic (sroc) space and Spearman s correlation coefficient. The shoulder-arm pattern in the sroc space and a strong positive Spearman correlation coefficient indicate the existence of the threshold effect. 16,17 Publication bias was investigated using Deeks funnel plot asymmetry test, which was conducted using a regression of the diagnostic log odds ratio against 1/sqrt (effective sample size) weighting by effective sample size, with P \.10 for the slope coefficient indicating significant asymmetry. 18 The random effect model was applied to pool sensitivity, specificity, positive likelihood ratio (LR), negative LR, and diagnostic odds ratio (DOR). The sroc curves were constructed for the pooled DOR of individual studies. Subgroup analyses were performed to explore the source of the heterogeneity. Subgroup analyses were conducted based on study origin, evaluation technique, and study quality. Statistical analyses of heterogeneity, threshold effect, pooled result sensitivity Included Eligibility Screening Iden fica on Records iden fied through database searching (n =117) Records a er duplicates removed (n = 86) Records screened (n = 56) Full-text ar cles assessed for eligibility (n = 24) Studies included in qualita ve synthesis (n = 7) Studies included in quan ta ve synthesis (meta-analysis) (n = 7) Records excluded based on tle and abstract (n = 32) Full-text ar cles excluded With reasons (n = 17) Not evalua on the diagnos c; performance of CEUS on thyroid nodules (n = 9); Updated (n = 3); Not prospec ve (n = 3); Unable to create 2x2 table (n = 2) Figure 1. Flowchart of studies included in this meta-analysis. analyses, and subgroup analyses were performed using Meta-Disc (version 1.4). The Deeks funnel plot asymmetry test was plotted using Stata (version 12). The protocol was approved by the local institutional review board. Results Identification of Eligible Studies Figure 1 shows a flowchart depicting the selection procedure of studies. Using the predefined search strategy, 117 publications were identified. By successively reviewing the titles, abstracts, and full texts, 7 studies ultimately fulfilled the inclusion criteria and were included in our meta-analysis Study Characteristics Table 1 shows the summary information of the studies included in the meta-analysis. The studies were published between 2008 and 2014, with 3 studies performed in China, 3 conducted in Italy, and 1 study from Austria. The number of lesions examined in the studies ranged from 23 to 175, for a total of 597 lesions. Of these, 340 were benign and 257 were malignant. Qualitative evaluations of CEUS were conducted in 4 studies, whereas quantitative evaluations were performed in 3 studies. Five studies used surgical pathology as the standard reference, and 2 studies used both surgical pathology and biopsy. Detailed information of the QUADAS evaluation of each study is shown in Table 2. The QUADAS evaluation scores ranged from 9 to 12. Three studies scored 11, and 4 studies scored \11.

3 Yu et al 911 Table 1. Characteristics of Included Studies. Author Publication Year Country Age, Range Total Lesions, n Malignant Lesions, n Benign Lesions, n Gold Standard Way of Evaluation Ferrari et al Italy Surgical pathology 1 biopsy Quantitative Zhang et al China Surgical pathology Qualitative Nemec et al Austria N Surgical pathology Quantitative Cantisaniet al Italy Surgical pathology Qualitative Giusti et al Italy N Surgical pathology Quantitative Ma et al China Surgical pathology Qualitative Deng et al China Surgical pathology 1 biopsy Qualitative Abbreviation: N, not mentioned. Table 2. Quality Assessment of Included Studies by QUADAS Tool. Question of Quality Assessment Ferrari et al 13 Zhang et al 7 Nemec et al 8 Cantisani et al 9 Giusti et al 10 Ma et al 12 Deng et al 11 Q1 Patient spectrum Y Y Y Y Y Y Y Q2 Reporting of selection criteria N Y Y Y Y Y Y Q3 Appropriate reference standard Y Y Y Y Y Y Y Q4 Absence of disease progression bias U U Y Y U U U Q5 Absence of partial verification bias Y N Y Y N Y Y Q6 Absence of differential verification bias N Y Y Y Y Y U Q7 Absence of incorporation bias Y Y Y Y U Y U Q8 Description of test execution detail Y Y Y Y Y Y Y Q9 Description of reference execution detail U U U U U U U Q10 Absence of test review bias Y Y Y Y Y Y Y Q11 Absence of diagnostic review bias U Y U U U Y U Q12 Absence of clinical review bias Y Y Y Y Y Y Y Q13 Reporting of uninterpretable/intermediate results Y Y Y Y Y Y Y Q14 Withdrawals Y Y Y Y Y Y Y Abbreviations: N, no; U, unclear; Y, yes. Diagnostic Performance The random effect model was used to generate the pooled result. The pooled sensitivity, specificity, positive LR, and negative LR of CEUS for differentiation of malignant and benign thyroid nodules were (95% confidence interval [CI], ), (95% CI, ), (95% CI, ), and (95% CI, ), respectively. The pooled DOR was (95% CI, ), which is calculated as (TP 3 TN)/(FP 3 FN) and defined as the odds of having a positive test result in a patient with disease compared with the odds of a positive test result in a patient without disease. The area under the curve (AUC) was (Figure 2). The forest plots of sensitivity, specificity, positive LR, negative LR, and DOR with the corresponding 95% CI values of the included studies are shown in Figure 3. Heterogeneity Analyses A homogeneity test of the DOR showed Q = (P =.029) and I 2 = 57.4%, which indicates heterogeneity exists Figure 2. Summary receiver operating characteristic curve of contrast-enhanced ultrasound for assessing the thyroid nodules.

4 912 Otolaryngology Head and Neck Surgery 151(6) Figure 3. (continued) across the included studies. To explore the sources of heterogeneity, we primarily analyzed the threshold effect. However, there was no shoulder-arm sign shown on the sroc space (Figure 4), and the Spearman correlation coefficient was (P =.337), indicating there was no significant threshold effect in the studies and suggesting that there are other factors resulting in heterogeneity between the included studies. The results of the subgroup way of evaluation showed that qualitative evaluation acquired better sensitivity, specificity, and DOR compared with quantitative evaluation. In addition, the heterogeneity was eliminated when the qualitative evaluation studies were excluded. Detailed results of subgroup analyses of the included studies are presented in Table 3. Publication Bias According to the Deeks funnel plot asymmetry test, there was no significant publication bias among the eligible studies (P =.193). The Deeks funnel plot is shown in Figure 5. Discussion Contrast-enhanced ultrasound is a recently developed noninvasive ultrasound technique that can assess both the microand macro-vascularization of the tumor, which has been proven in different applications. 7 To the best of our knowledge, this is the first meta-analysis to assess the diagnostic performance of CEUS in differentiating benign and malignant thyroid nodules. The pooled results showed that thyroid nodules can be diagnosed by CEUS with pooled sensitivity, specificity, positive LR,

5 Yu et al 913 Figure 3. The forest plots of sensitivity (A), specificity (B), positive likelihood ratio (C), negative likelihood ratio (D), and diagnostic odds ratio (D) of this meta-analysis. and negative LR values of 0.853, 0.876, 5.822, and 0.195, respectively. These data suggest CEUS has high sensitivity and specificity in diagnosing thyroid nodules. The AUC is , and the DOR is , which are the overall evaluation indicators of diagnostic tests and confirm the high accuracy of CEUS in differentiating malignant and benign thyroid nodules. Heterogeneity test results indicated moderate heterogeneity. We found that there is no significant threshold effect among the included studies. Thus, subgroup analyses were conducted to seek the source of heterogeneity. In subgroup analyses, the results showed that the heterogeneity was eliminated in pooled estimates when the qualitative evaluation studies were excluded. The reappraised pooled results still suggested a high accuracy of CEUS in diagnosing thyroid nodules (AUC = and DOR = ). Two methods were used in the included studies: qualitative evaluation and quantitative evaluation. There were 3 quantitative studies and 4 qualitative studies included in our meta-analysis. However, there are no standards for quantitative studies or qualitative studies. In our meta-analysis, the 3 quantitative studies took the peak enhancement and polyphasic washout curve as the diagnostic standard, whereas the quantitative studies made the diagnosis based on different standards, including incomplete ring enhancement, heterogeneous enhancement, and hypoenhancement. According to our subgroup analyses, the CEUS evaluation method for diagnosing thyroid nodules is likely the major source of heterogeneity. Published studies have shown various CEUS Figure 4. The receiver operating characteristic plane of the metaanalysis. Sensitivity against (1 specificity) of each study of contrast-enhanced ultrasound in diagnosing the thyroid lesions. features of malignant thyroid nodules. In quantitative evaluations, polyphasic washout curves, earlier arrival time, and time to peak were associated with malignancy In the qualitative evaluations, heterogeneous enhancement23,24

6 914 Otolaryngology Head and Neck Surgery 151(6) Table 3. Results of Subgroups. a Subgroups of Studies No. of Studies Sensitivity Specificity AUC (Q*) DOR Heterogeneity (P) I 2,% Qualitative evaluation (0.7376) Quantitative evaluation (0.8464) Asia region (0.7666) Non-Asia region (0.8058) Score (0.8869) Score \ (0.8349) Pathology (0.7740) Pathology 1 biopsy 2 a The diagnostic odds ratio (DOR) is calculated as (true-positive 3 true-negative)/(false-positive 3 false-negative). data, analysis and interpretation of data, revising the article; Taotao Chen, acquisition of data, analysis and interpretation of data, revised article. Disclosures Competing interests: None. Sponsorships: None. Funding source: None. References Figure 5. Deek s funnel plot of publication bias. and washout in the late phase 22,24 were considered signs of malignancy. Among these published features that suggest malignancy, no single feature was sufficiently sensitive and specific enough for malignancy. More studies are needed to explore an appropriate diagnostic standard for CEUS in diagnosing thyroid nodules. Our meta-analysis has several limitations. First, our meta-analysis consisted of only 7 studies. The small number of studies might reduce the power of the tests of publication bias and heterogeneity. 25 Second, the included studies used different diagnostic standards. Finally, the methodological quality of the included studies was not particularly high. In conclusion, CEUS is a promising noninvasive technique for the differential diagnosis of benign and malignant thyroid nodules that may be a valuable supplemental method to fine-needle aspiration. However, the results should be interpreted with caution because of the potential bias of the included studies. High-quality studies with larger sample sizes are necessary to confirm these results and improve the diagnostic performance of CEUS in diagnosing thyroid nodules. Author Contributions Dongmei Yu, conception and design, acquisition of data, analysis and interpretation of data, drafting and revising the article, final approval of the version to be published; Yuna Han, acquisition of 1. Guth S, Theune U, Aberle J, et al. Very high prevalence of thyroid nodules detected by high frequency (13 MHz) ultrasound examination. Eur J Clin Invest. 2009;39: Cooper DS, Doherty GM, Haugen BR, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2006;16: British Thyroid Association. Guidelines for the Management of Thyroid Cancer in Adults. February 15, National Comprehensive Cancer Network. NCCN Guidelines on Thyroid Carcinoma, Version 2. For Washington, PA: National Comprehensive Cancer Network; Moon WJ, Baek JH, Jung SL, et al. Ultrasonography and the ultrasound-based management of thyroid nodules: consensus statement and recommendations. Korean J Radiol. 2011;12: Anil G, Hegde A, Chong FH.Thyroid nodules: risk stratification for malignancy with ultrasound and guided biopsy. Cancer Imaging. 2011;11: Zhang B, Jiang YX, Liu JB, et al. Utility of contrast-enhanced ultrasound for evaluation of thyroid nodules. Thyroid. 2010; 20: Nemec U, Nemec SF, Novotny C, et al. Quantitative evaluation of contrast-enhanced ultrasound after intravenous administration of a microbubble contrast agent for differentiation of benign and malignant thyroid nodules: assessment of diagnostic accuracy. Eur Radiol. 2012;22: Cantisani V, Consorti F, Guerrisi A, et al. Prospective comparative evaluation of quantitative-elastosonography (Q-elastography) and contrast-enhanced ultrasound for the evaluation of thyroid nodules: preliminary experience. Eur J Radiol. 2013;82:

7 Yu et al Giusti M, Orlandi D, Melle G, et al. Is there a real diagnostic impact of elastosonography and contrast-enhanced ultrasonography in the management of thyroid nodules? J Zhejiang Univ Sci B. 2013;14: Deng J, Zhou P, Tian SM, Zhang L, Li JL, Qian Y. Comparison of diagnostic efficacy of contrast-enhanced ultrasound, acoustic radiation force impulse imaging, and their combined use in differentiating focal solid thyroid nodules. PloS One. 2014;9:e Ma JJ, Ding H, Xu BH, et al. Diagnostic performances of various gray-scale, color Doppler, and contrast-enhanced ultrasonography findings in predicting malignant thyroid nodules. Thyroid. 2014;24: Ferrari FS, Megliola A, Scorzelli A, Guarino E, Pacini F. Ultrasound examination using contrast agent and elastosonography in the evaluation of single thyroid nodules: preliminary results. J Ultrasound. 2008;11: Whiting P, Rutjes AW, Reitsma JB, et al. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol. 2003;3: Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327: Moses LE, Shapiro D, Littenberg B. Combining independent studies of a diagnostic test into a summary curve: data-analytic approaches and some additional considerations. Stat Med. 1993;12: Dinnes J, Deeks J, Kirby J. A methodological review of how heterogeneity has been examined in systematic reviews of diagnostic test accuracy. Health Technol Assess. 2005;9: Deeks JJ, Macaskill P, Irwig L. The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol. 2005;58: Spiezia S, Farina R, Cerbone G, et al. Analysis of color Doppler signal intensity variation after Levovist injection: a new approach to the diagnosis of thyroid nodules. J Ultrasound Med. 2001;20: Argalia G, De Bernardis S, Mariani D, et al. Ultrasonographic contrast agent: evaluation of time-intensity curves in the characterisation of solitary thyroid nodules. Radiol Med. 2002;103: Appetecchia M, Bacaro D, Brigida R, et al. Second generation ultrasonographic contrast agents in the diagnosis of neoplastic thyroid nodules. J Exp Clin Cancer Res. 2006;25: Hornung M, Jung EM, Georgieva M, et al. Detection of microvascularization of thyroid carcinomas using linear high resolution contrast-enhanced ultrasonography (CEUS). Clin Hemorheol Microcirc. 2012;52: Bartolotta TV, Midiri M, Galia M, et al. Qualitative and quantitative evaluation of solitary thyroid nodules with contrast-enhanced ultrasound: initial results. Eur Radiol. 2006;16: Agha A, Jung EM, Janke M, et al. Preoperative diagnosis of thyroid adenomas using high resolution contrast-enhanced ultrasound (CEUS). Clin Hemorheol Microcirc. 2013;55: Piscaglia F, Nolsoe C, Dietrich CF, et al. The EFSUMB guidelines and recommendations on the clinical practice of contrast enhanced ultrasound (CEUS): update 2011 on non-hepatic applications. Ultraschall in der Medizin. 2012;33:33-59.