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Original Article
EP14504.OR
THE MAXIMAL STIFFNESS EVALUATION BY REAL TIME ULTRASOUND ELASTOGRAPHY, AN IMPROVED TOOL FOR THE DIFFERENTIAL DIAGNOSIS OF THYROID NODULES
Flavia Magri MD, PhD1, Spyridon Chytiris MD1, Francesca Zerbini MD1, Valentina Capelli MD1, Margherita Gaiti MD1, Andrea Carbone MD1, Rodolfo Fonte MD1, Alberto Malovini PhD2, Mario Rotondi MD, PhD1, Riccardo Bellazzi PhD3, Luca Chiovato MD, PhD1
Running title: Elastography maximal stiffness
From: 1 Unit of Internal Medicine and Endocrinology, IRCCS Fondazione Salvatore Maugeri; Department of Internal Medicine and Medical Therapy, University of Pavia, Italy; 2 Laboratorio di Informatica e Sistemistica per la Ricerca Clinica, IRCCS Fondazione S.Maugeri, Pavia; 3 Laboratorio di Informatica Biomedica, Dipartimento di Ingegneria Industriale e dell'Informazione Università di Pavia.
Correspondence Address: Luca Chiovato, MD, PhD, Unit of Internal Medicine and Endocrinology, Fondazione Salvatore Maugeri IRCCS, Chair of Endocrinology, University of Pavia Via S. Maugeri 10, I-27100, Pavia, Italy Email: [email protected]
DOI:10.4158/EP14504.OR © 2014 AACE.
Abstract Objective: Aim of the study was to evaluate the diagnostic performance of a new ultrasound (US) elastography (USE) parameter based on the measurement of the percentage of maximal stiffness within a nodule as compared with the already established elastographic strain index (SI), and to investigate their diagnostic performance according to nodule size. Methods: The study included 218 nodules. Each nodule underwent conventional ultrasound (US), USE evaluation and fine needle aspiration cytology (FNAC). Thyroid nodules were further stratified according to their size (G1< 1 cm, G2= 1-2 cm, G3> 3 cm). USE evaluation comprised the measurement of the percentage of the areas included in the region of interest corresponding to the maximal stiffness (% Index) and of the SI. Results: The % Index and of the SI were significantly higher in malignant than in benign thyroid nodules, and both measurements displayed a good diagnostic performance (SI sensitivity and specificity = 0.66 and 0.90, respectively; % index sensitivity and specificity = 0.76 and 0.89, respectively). Compared with SI, the % Index was more informative, both in the whole group of thyroid nodules (OR[95%CI]=18.68[6.06-63.49], p=1.49x10-8, vs OR[95%CI]=26.15[8.01-102.87], p=3.41x10-10 respectively) and in the G1 and G2 subgroups. Conclusion: The % Index is a stronger predictor of nodule malignancy than both the SI and the conventional US signs. This is particularly true in nodules smaller than 1 cm, which are more difficult to be explored both by conventional US and by FNAC.
Key words: thyroid, real time elastography, thyroid nodule, thyroid cancer Word Count: Text 2667
DOI:10.4158/EP14504.OR © 2014 AACE.
Abbreviations: US = Ultrasound, USE = Ultrasound elastography, SI = Strain index, FNAC = Fine needle aspiration cytology, % Index = Percentage of maximal stiffness within the nodule, ATA = American Thyroid Association, MCC = Mattew’s Correlation Coefficient, AUROC = Area Under the ROC Curve, OR = Odds ratio, PPV = positive predictive value, NPV = negative predictive value, RTE = Real time elastography.
Introduction Thyroid nodules affect up to 50% of people living in iodine deficient areas [1], and are more common in females than in males (F:M ratio=4:1) . Thyroid nodules are often incidentally discovered by palpation and more frequently by thyroid ultrasound (US), their incidence increases in relation to age, previous neck irradiation and some clinical conditions such as acromegaly [2-4]. The differential diagnosis between benign and malignant thyroid nodules is crucial due to their high prevalence in the general population and the increasing incidence of thyroid cancer observed in the last 20 years [5-7]. Fine-needle aspiration cytology (FNAC) is the gold standard in the differential diagnosis of thyroid nodules [1]. FNAC is a highly specific and sensitive tool, but it is also an expensive and minimally invasive procedure. Conventional US is usually employed in the first step evaluation of thyroid nodules. Five US features of thyroid nodules (hypo-echogenicity, irregular margins, micro-calcifications, increased vascularization, and regional lymphadenopathy) are well known predictors of malignancy. [8-10].
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However none of them, by itself or in combination, has an adequate sensitivity or specificity [1114]. Because a hard consistency of the nodule is usually associated with an increased risk of malignancy, ultrasound elastography (USE) was recently introduced in the diagnostic work up of thyroid nodules. The latest American Thyroid Association (ATA) Guidelines mentioned elastography as a promising technique, still requiring validation [11]. Several studies showed that USE can detect thyroid malignancy with high sensitivity and specificity even in case of indeterminate or non diagnostic cytology [15-21], although other reports challenged these findings [22,23]. Using a qualitative (elasticity score) or a semi-quantitative approach, the Strain index (SI), USE was reported to be able of predicting thyroid malignancy [15-18]. However, real time techniques suffer from several limitations mainly represented by their operator dependency, the presence of calcifications or cystic fluid within the nodule, the nodule size and the position within the gland. Interfering effects from carotid artery pulsation may also hamper the procedure [16,24,25]. Despite these limitations, we previously demonstrated that the SI owns an excellent diagnostic performance in predicting thyroid malignancy, which was higher than that provided by any conventional US sign [15]. Aim of the present study was: i) to evaluate, as compared with the SI, the diagnostic performance of a new USE parameter based on the measurement of the percentage of maximal stiffness within the nodule, and ii) to investigate whether nodule size could affect the diagnostic accuracy of these two USE measurements.
Subjects and methods The recruitment of cases was carried out from December 2013 to February 2014, and involved the examination of 250 consecutive patients harbouring one or more thyroid nodules. The total number DOI:10.4158/EP14504.OR © 2014 AACE.
of evaluated nodules was 296. Data concerning family and personal history were recorded. The serum levels of TSH, FT4, FT3, calcitonin, anti-thyroglobulin and anti-thyroid-peroxidase antibodies were also measured. Before FNAC, a conventional US and the USE evaluation were performed. Exclusion criteria for USE were pure cystic lesions, insufficient normal tissue around the target nodule, the occurrence of isthmic and para-isthmic nodules due to the interference produced by the tracheal cartilage. Two hundred and twelve patients (median age = 57 yrs., 25th and 75th percentile = 44-66 yrs.) fulfilled the inclusion criteria. A total of 243 thyroid nodules were evaluated for the study. All patients gave their written informed consent to participate in the study and to allow the future use of their clinical data for research purposes according to the local ethics committee and the guidelines of the Declaration of Helsinki. As previously described [15], thyroid US evaluation was performed using a real-time US device equipped with a linear transducer operating at 7.5 MHz (Mylab 70XVG). Thyroid nodules were carefully examined for the following US features: nature, i.e. solid, cystic or mixed; echogenicity, i.e. hyperechoic, isoechoic or hypoechoic compared with normal parenchyma and with neck muscles; size; homogeneity, i.e. homogeneous or inhomogeneous; micro-calcifications (hyper-echoic spots < 2 mm without acoustic shadowing); presence of regular or irregular margins; halo sign, i.e. presence or absence of an hypoechoic rim; color-flow Doppler pattern. The nodule volume was calculated by the elliptical shape volume formula (length x width x depth x 0.479). All thyroid US scans were performed by the same operator (S.C.), who had a more than 5-year experience with thyroid imaging. The same US device was used to perform USE, according to the technique described by Cakir et al [26] (see for detail [15] ). Briefly, the operator, after having achieved the optimal level of compression, used an electronic box, which included the selected nodule and a sufficient amount of surrounding parenchyma. Within this box the operator identified two regions of interest: the first one corresponding to the nodule and the second one corresponding to the softest area of normal DOI:10.4158/EP14504.OR © 2014 AACE.
parenchyma, identified by its red color on elastosonogram. The SI was calculated as the ratio of thyroid nodule strain over the strain of the softest area of parenchyma. In the present study the software employed for calculating the SI was improved by allowing the measurement of the percentage of all areas included in the region of interest (nodule), which had the maximal stiffness (namely the percentage of pure blue colour within the nodule). This measurement was defined as the percent Index (% Index). Fig. 1 shows the elastographyc strain index and % Index in a benign (panel A) and a malignant (panel B) thyroid nodule. FNAC was performed according to the current guidelines [27] under US guidance by a skilled endocrinologist using a 23-gauge needle attached to a 2.5 ml syringe. Cytological samples were classified into 6 classes [28]: non-diagnostic (THY 1, no. = 16; accounting for 6.6%), which were excluded from the study; benign (THY2, no. = 193; 79.5%); indeterminate follicular lesion (THY3a and THY3b, no. = 15; 6.1%), suspicious for malignancy (THY4 no. = 5; 2.1%); malignant (THY5, no. = 14; 5.7%). Nine of the 15 THY3 nodules were excluded from the study due to the lack of corresponding histologic data, while 6 (THY3a = 3 and THY3b = 3) were included in the study. At histology, 2 malignant lesions and 4 follicular adenomas were diagnosed among the 6 THY3 operated nodules. All nodules with a THY4 or THY5 cytology were confirmed as malignant lesions by histology on surgical specimens. The final study group included 218 thyroid nodules. Thyroid nodules were further stratified according to their size: G1 < 1 cm, G2 = 1-2 cm, G3 > 3 cm. Benign thyroid nodules, as assessed by FNAC, were submitted to a follow-up observation consisting in periodical physical examination and conventional US and USE evaluation. The time interval between subsequent controls ranged from 6 to 12 months. FNAC was repeated in case of increased size, as indicated in the ATA guidelines [11,27], or of changes in US or USE features. Until now, no change in the diagnosis of benign nodule occurred.
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Statistical analysis Since most of the quantitative variables deviated significantly from normality (Shapiro-Wilk p < 0.05), all distributions were described as median (25th – 75th percentiles) and non-parametric tests were applied. The Wilcoxon Rank-Sum test for paired samples was applied to test for statistically significant differences in terms of distribution of quantitative variables between two experimental conditions. The Spearman test was applied to evaluate the correlation between quantitative variables. The Fisher’s Exact test was used to evaluate the association between categorical variables. Stepwise logistic regression was used to identify the most informative variable being relevant for the diagnosis of thyroid nodules. The best cut-off values for the % Index and the SI in discriminating malignant from benign nodules were estimated by the following resampling procedure repeated 1,000 times: - On each training set: Record the values that the variable may assume. - On the corresponding test set: Estimate and record the predictive accuracy (expressed in terms of Mattew’s Correlation Coefficient - MCC) of each value observed in the training set. The most informative cut-off was estimated by taking the values of % Index or SI, which reached the maximum median MCC over the 1,000 re-samplings. Statistical analyses were performed by the R software v3.0.2 (www.r-project.org/).
Results Diagnostic performance of USE strain index and % index Table I summarizes the clinical data, the conventional US signs and the USE findings, expressed as % Index and SI, of the 218 thyroid nodules included in the study. Malignant nodules had a significantly higher prevalence of three US signs of malignancy (hypo-echogenicity, irregular borders and micro-calcifications). Although not significant, a smaller volume of the nodule was also DOI:10.4158/EP14504.OR © 2014 AACE.
associated with malignancy. When the maximum diameter was considered, nodules larger than 1 cm (i.e. belonging to the G2 and G3 subgroups) had a statistically significant lower risk of being malignant with respect to those belonging to the G1 subgroup (OR = 0.175, 95 % CI = 0.056 – 0.553, p = 0.002 and OR = 0.238, 95 % CI = 0.062 – 0.853, p = 0.029 for G2 and G3 respectively). Moreover, nodules smaller than 1 cm in diameter had a 5-fold increased risk of being malignant with respect to those with a diameter greater than 1 cm (OR = 5.17, 95% CI = 1.737 – 14.598, p = 0.002). With specific regard to USE evaluation, the median values of both % Index and SI were significantly higher in malignant than in benign thyroid nodules. The values of the % Index and of the SI were strongly correlated (r = 0.87, p< 3x10-6) between each other. As shown in Fig 2a , the Area Under the ROC Curve (AUROC) estimates corresponding to the two USE parameters were also very similar. When the % Index and the SI were analyzed in relation to the nodule size, both parameters were strongly predictive of malignancy in thyroid nodules larger than 1 cm (G2 and G3 subgroups), but not in smaller thyroid nodules (G1 subgroup) (Fig. 2b and 2c). Identification and evaluation of the USE strain index and % index cut-off The identification of cut-off values for the % Index and the SI was performed by a resampling procedure repeated 1000 times, as described in the statistical analysis section. The most informative cut-off values discriminating benign from malignant thyroid nodules were 57.6 and 4.24 for % Index and SI, respectively (Fig. 3). The diagnostic performance of the cut-off values of the % Index and of the SI was then tested both in the whole study group of thyroid nodules and in the subgroups stratified according to the nodule size (G1, G2 and G3). Results were expressed in terms of Mattew’s Correlation Coefficient (MCC), Area Under the ROC Curve (AUROC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and F-Measure. As summarized in Table II, both the % Index and the SI cut-offs were highly informative for predicting nodule malignancy. In particular, when compared with the SI cut-off, the % Index cut-off reached DOI:10.4158/EP14504.OR © 2014 AACE.
slightly higher discriminative performances in the whole study group and in the G1 and G2 subgroups, being superimposable in the G3 subgroup. Univariate association tests showed that the % Index cut-off > 57.6 was the USE parameter with the strongest impact on the risk of malignancy when compared with the SI cut-off > 4.24 (OR [95%CI] = 26.15 [8.01-102.87], p=3.41 x 10-10 vs OR [95%CI] = 18.68 [6.06-63.49], p=1.49 x 10-8, respectively). As shown in Table III, stepwise logistic regression starting from a full model represented by the complete set of covariates reported in table I revealed that % Index cut-off, age, irregular margins, micro-calcifications are the most informative predictors of the risk of thyroid malignancy. These statistics also suggest that the % index cut-off is more informative than the SI cut-off even when other predictors are taken into account in a multivariate approach. Discussion In this study we evaluated the diagnostic performance of a new USE parameter based on the measurement of the percentage of maximal stiffness within a nodule (defined as % Index) with the already established elastographic strain index (SI). As recently shown by our group, the SI displays a high sensitivity, specificity and negative predictive value for the diagnosis of thyroid malignancy [15]. These data were confirmed in the present study. The % Index, obtained using a different software, but during the same procedure as SI, evaluates the percentage of the area with a maximal stiffness within a nodule. The two elastographic measurements were found to be strongly correlated between each other. However, the % Index, when compared with the SI, was more informative. This is probably because the % Index highlights the hardest parts of the region of interest, while the SI considers the mean stiffness of the nodule. To the best of our knowledge, the present study is the first one validating the % index as a reliable tool in the differential diagnosis of thyroid nodules. Indeed, the median % Index was significantly higher in malignant than in benign nodules. Moreover, when compared with the SI and with conventional DOI:10.4158/EP14504.OR © 2014 AACE.
US signs in a multivariate analysis, the % Index was a significantly stronger predictor of malignancy. Compelling evidence indicates that nodule size, although considered by most current guidelines a criterion for selecting nodules to be biopsied, is not a reliable predictor of malignancy [11,17]. Moreover, papillary micro-carcinomas encompass all sorts of histotypes, including the poorly circumscribed and/or the infiltrative ones [29]. Micro-carcinomas may not exhibit obvious changes in morphology and are difficult to be recognized by conventional US [30]. Previous studies using USE in the differential diagnosis of small thyroid nodules also gave conflicting results. Cappelli et al. suggested that real time elastography (RTE) is a useful tool even in small (3-10 mm of maximum diameter) thyroid nodules, having a sensitivity of 91% and a specificity of 89% [31]. By applying the same procedure to a surgical series of patients with single thyroid nodules smaller than 10 mm, Wang et al. found a sensitivity of 90.6%, a specificity of 89.5% and an accuracy of 90.2 %. The positive and negative predictive values were 93.5 % and 85.0 %, respectively [30]. Less promising results were reported by Liu et al. in a study comparing the diagnostic performance of shear wave elastography (SWE) and RTE in nodules of different size. In this study, RTE had a low sensitivity (88.9 %) and specificity (70.0 %) in nodules smaller than 1 cm; the diagnostic performance of SWE was even poorer, with a sensitivity of 44.4% and a specificity of 90% [32]. In the present study, the discriminating capability of both the % Index and the SI was evaluated in nodules stratified according to their increasing size. In thyroid nodules smaller than 1 cm, the % Index was found to be the most accurate predictor of malignancy. Thus, the % index is a reliable adjunctive diagnostic tool for identifying malignant thyroid nodules. However, it still suffers from several limitations, which are shared by other USE techniques: operator dependency, interfering effects produced by calcifications or cystic fluids within the nodule, nodule size and position within the gland, and carotid artery pulsation [24]. In the present DOI:10.4158/EP14504.OR © 2014 AACE.
study we excluded 53 thyroid nodules (17.8% of the initial sample) from USE evaluation. Despite this limitation, the semi-quantitative elastographic approach, based on the evaluation of the SI and of the percentage of all areas included in the nodule with the maximal stiffness (% Index), allowed to better standardize the procedure with a reduction of the inter-observer variability, as well as of the variability in data acquisition, which often limits the results of the elastographic evaluation. The great number of papers addressing this issue demonstrates its relevance [33-35]. In conclusion, the percentage of the area included in the region of interest (nodule) corresponding to the maximal stiffness (% index) is a useful parameter to be used in the differential diagnosis of thyroid nodules and for selecting the ones to be submitted to FNAC. Multi-center prospective studies are needed to validate our results in a larger population. If our data were confirmed, the % Index might be considered as an adjunctive diagnostic tool to conventional US in the setting of diagnostic thyroid nodule management.
Conflict of Interest: There were no grants or fellowship support in writing of this manuscript. The authors have no conflict of interest regarding the publication of this article.
DOI:10.4158/EP14504.OR © 2014 AACE.
REFERENCES 1.
Hegedus L. Clinical practice. The thyroid nodule. N Engl J Med 2004;351:1764-1771
2.
Dean DS, Gharib H. Epidemiology of thyroid nodules. Best Pract Res Clin Endocrinol Metab 2008;22:901-911
3.
Malboosbaf R, Hosseinpanah F, Mojarrad M, Jambarsang S, Azizi F. Relationship between goiter and gender: a systematic review and meta-analysis. Endocrine 2013;43:539547
4.
Guo H, Sun M, He W, et al. The prevalence of thyroid nodules and its relationship with metabolic parameters in a Chinese community-based population aged over 40 years. Endocrine 2014;45:230-235
5.
Enewold L, Zhu K, Ron E, et al. Rising thyroid cancer incidence in the United States by demographic and tumor characteristics, 1980-2005. Cancer Epidemiol Biomarkers Prev 2009;18:784-791
6.
Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913-2921
7.
Davies L, Welch HG. Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg 2014;140:317-322
8.
Moon HJ, Sung JM, Kim EK, et al. Diagnostic performance of gray-scale US and elastography in solid thyroid nodules. Radiology 2012;262:1002-1013
9.
Asteria C, Giovanardi A, Pizzocaro A, et al. US-elastography in the differential diagnosis of benign and malignant thyroid nodules. Thyroid 2008;18:523-531
10.
Khoo ML, Asa SL, Witterick IJ, Freeman JL. Thyroid calcification and its association with thyroid carcinoma. Head Neck 2002;24:651-655
DOI:10.4158/EP14504.OR © 2014 AACE.
11.
Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19:1167-1214
12.
Rago T, Vitti P. Diagnostic role of ultrasound and elastosonography in nodular goiter. Best Pract Res Clin Endocrinol Metab 2014;28:519-529
13.
Rago T, Vitti P, Chiovato L, et al. Role of conventional ultrasonography and color flowdoppler sonography in predicting malignancy in 'cold' thyroid nodules. Eur J Endocrinol 1998;138:41-46
14.
Gharib H, Papini E, Paschke R, et al. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. J Endocrinol Invest 2010;33:51-56
15.
Magri F, Chytiris S, Capelli V, et al. Comparison of elastographic strain index and thyroid fine-needle aspiration cytology in 631 thyroid nodules. J Clin Endocrinol Metab 2013;98:4790-4797
16.
Grazhdani H, Cantisani V, Lodise P, et al. Prospective evaluation of acoustic radiation force impulse technology in the differentiation of thyroid nodules: accuracy and interobserver variability assessment. J Ultrasound 2014;17:13-20
17.
Bojunga J, Herrmann E, Meyer G, et al. Real-time elastography for the differentiation of benign and malignant thyroid nodules: a meta-analysis. Thyroid 2010;20:1145-1150
18.
Rago T, Santini F, Scutari M, Pinchera A, Vitti P. Elastography: new developments in ultrasound for predicting malignancy in thyroid nodules. J Clin Endocrinol Metab 2007;92:2917-2922
DOI:10.4158/EP14504.OR © 2014 AACE.
19.
Rago T, Vitti P. Role of thyroid ultrasound in the diagnostic evaluation of thyroid nodules. Best Pract Res Clin Endocrinol Metab 2008;22:913-928
20.
Magri F, Chytiris S, Capelli V, et al. Shear wave elastography in the diagnosis of thyroid nodules: feasibility in the case of coexistent chronic autoimmune Hashimoto's thyroiditis. Clin Endocrinol (Oxf) 2012;76:137-141
21.
Rago T, Scutari M, Santini F, et al. Real-time elastosonography: useful tool for refining the presurgical diagnosis in thyroid nodules with indeterminate or nondiagnostic cytology. J Clin Endocrinol Metab 2010;95:5274-5280
22.
Unlütürk U, Erdoğan MF, Demir O, Güllü S, Başkal N. Ultrasound elastography is not superior to grayscale ultrasound in predicting malignancy in thyroid nodules. Thyroid 2012;22:1031-1038
23.
Kim H, Kim JA, Son EJ, Youk JH. Quantitative assessment of shear-wave ultrasound elastography in thyroid nodules: diagnostic performance for predicting malignancy. Eur Radiol 2013;23:2532-2537
24.
Cantisani V, Lodise P, Grazhdani H, et al. Ultrasound elastography in the evaluation of thyroid pathology. Current status. Eur J Radiol 2014;83:420-428
25.
Cantisani V, Lodise P, Di Rocco G, et al. Diagnostic Accuracy and Interobserver Agreement of Quasistatic Ultrasound Elastography in the Diagnosis of Thyroid Nodules. Ultraschall Med 2014
26.
Cakir B, Aydin C, Korukluoğlu B, et al. Diagnostic value of elastosonographically determined strain index in the differential diagnosis of benign and malignant thyroid nodules. Endocrine 2011;39:89-98
27.
Gharib H, Papini E, Paschke R, et al. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association Medical guidelines
DOI:10.4158/EP14504.OR © 2014 AACE.
for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. Endocr Pract 2010;16:468-475 28.
London RCoPo. Guidelines for the management of thyroid cancer. In: The Lavenham Press, Suffolk, 2nd ed.; 2007
29.
Soares P, Celestino R, Gaspar da Rocha A, Sobrinho-Simões M. Papillary thyroid microcarcinoma: how to diagnose and manage this epidemic? Int J Surg Pathol 2014;22:113-119
30.
Wang Y, Dan HJ, Dan HY, Li T, Hu B. Differential diagnosis of small single solid thyroid nodules using real-time ultrasound elastography. J Int Med Res 2010;38:466-472
31.
Cappelli C, Pirola I, Gandossi E, et al. Real-time elastography: a useful tool for predicting malignancy in thyroid nodules with nondiagnostic cytologic findings. J Ultrasound Med 2012;31:1777-1782
32.
Liu BX, Xie XY, Liang JY, et al. Shear wave elastography versus real-time elastography on evaluation thyroid nodules: a preliminary study. Eur J Radiol 2014;83:1135-1143
33.
Cantisani V, Grazhdani H, Ricci P, et al. Q-elastosonography of solid thyroid nodules: assessment of diagnostic efficacy and interobserver variability in a large patient cohort. Eur Radiol 2014;24:143-150
34.
Calvete AC, Rodríguez JM, de Dios Berná-Mestre J, et al. Interobserver agreement for thyroid elastography: value of the quality factor. J Ultrasound Med 2013;32:495-504
35.
Ragazzoni F, Deandrea M, Mormile A, et al. High diagnostic accuracy and interobserver reliability of real-time elastography in the evaluation of thyroid nodules. Ultrasound Med Biol 2012;38:1154-1162
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Table I. Clinical data, conventional US signs of malignancy and USE strain index and % index values of patients with benign and malignant thyroid nodules. Data are expressed as median (interquartile range) or as percent
Thyroid nodules Malignant (n = 21) Benign (n = 197) Age (y) Gender (males) Strain Index (S.I.) % Index
p
50 (45, 60)
57 (44, 66.75)
0.078
4 (19.05)
45 (22.9)
0.789
5.36 (3.17, 6.12)
2.63 (2.11, 3.27) < 1 x 10 – 5
75.03 (57.69, 91.20)16.53 (6.13, 34.10) < 1 x 10 – 6
Hypo-ecogenicity (yes)
16 (76.19)
77 (39.4)
0.002
Irregular borders (yes)
8 (38.01)
1 (0.5)
< 1 x 10 – 6
Micro-calcifications (yes)
10 (47.62)
15 (7.6)
1.35 x 10 – 5
Vascularization (yes)
9 (42.86)
51 (25.8)
0.122
Volume (ml)
0.71 (0.34, 1.63)
0.85 (0.50, 2.13)
0.188
Max Diameter
1.21 (0.96, 1.86)
1.50 (1.23, 2.07)
0.050
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Table II. Diagnostic performance of USE SI and % index cut-offs in the whole study group and within the subgroups obtained on the basis of the nodule size (G1, G2 and G3). % Index ≥ 57.60 Group Whole G1 G2 G3
MCC 0.536 0.162 0.601 0.778
AUROC 0.828 0.581 0.941 0.889
Group MCC AUROC Whole 0.492 0.786 G1 -0.048 0.476 G2 0.589 0.899 G3 0.778 0.889
Sensitivity 0.762 0.429 1.000 0.800
Specificity 0.894 0.733 0.882 0.978
PPV 0.471 0.429 0.409 0.800
NPV 0.968 0.733 1.000 0.978
F-Measure 0.582 0.429 0.581 0.800
Strain Index ≥ 4.24 Sensitivity Specificity 0.667 0.906 0.286 0.667 0.889 0.909 0.800 0.978
PPV 0.467 0.286 0.444 0.800
NPV 0.957 0.667 0.990 0.978
F-Measure 0.549 0.286 0.593 0.800
MCC = Mattew’s Correlation Coefficient; AUROC = Area Under the ROC Curve; PPV = positive predictive value; NPV = negative predictive value
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Table III. Stepwise logistic regression including clinical, conventional US and USE parameters associated to thyroid malignancy
OR
L95
Age (y)
0.948
0.896 0.995
% Index ≥ 57.60
21.307 5.800 96.783
Irregular margins
47.125 5.037 1184.660 0.003
Micro-calcifications 8.534
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U95
1.820 44.552
p 0.040 1.33 x 10-5
0.007
Fig. 1 Examples of elastographyc strain index and % index measurements in benign (panel A) and malignant (panel B) thyroid nodule
A
B
Fig. 2. ROC curves corresponding to the SI and % index evaluation (continuous variables) in the whole study group (a) and in the three subgroups obtained according to nodule size (b)
a
b
Fig. 3. Identification of the USE SI and % index cut-off by resampling procedure repeated 1000times (Mathew’s Correlation Coefficient - MCC).
Dark continuous line=median p ) Blue line= 25th and 75th percentiles) Grey dotted line= range non outliner
Original Article
EP14504.OR
THE MAXIMAL STIFFNESS EVALUATION BY REAL TIME ULTRASOUND ELASTOGRAPHY, AN IMPROVED TOOL FOR THE DIFFERENTIAL DIAGNOSIS OF THYROID NODULES
Flavia Magri MD, PhD1, Spyridon Chytiris MD1, Francesca Zerbini MD1, Valentina Capelli MD1, Margherita Gaiti MD1, Andrea Carbone MD1, Rodolfo Fonte MD1, Alberto Malovini PhD2, Mario Rotondi MD, PhD1, Riccardo Bellazzi PhD3, Luca Chiovato MD, PhD1
Running title: Elastography maximal stiffness
From: 1 Unit of Internal Medicine and Endocrinology, IRCCS Fondazione Salvatore Maugeri; Department of Internal Medicine and Medical Therapy, University of Pavia, Italy; 2 Laboratorio di Informatica e Sistemistica per la Ricerca Clinica, IRCCS Fondazione S.Maugeri, Pavia; 3 Laboratorio di Informatica Biomedica, Dipartimento di Ingegneria Industriale e dell'Informazione Università di Pavia.
Correspondence Address: Luca Chiovato, MD, PhD, Unit of Internal Medicine and Endocrinology, Fondazione Salvatore Maugeri IRCCS, Chair of Endocrinology, University of Pavia Via S. Maugeri 10, I-27100, Pavia, Italy Email: [email protected]
DOI:10.4158/EP14504.OR © 2014 AACE.
Abstract Objective: Aim of the study was to evaluate the diagnostic performance of a new ultrasound (US) elastography (USE) parameter based on the measurement of the percentage of maximal stiffness within a nodule as compared with the already established elastographic strain index (SI), and to investigate their diagnostic performance according to nodule size. Methods: The study included 218 nodules. Each nodule underwent conventional ultrasound (US), USE evaluation and fine needle aspiration cytology (FNAC). Thyroid nodules were further stratified according to their size (G1< 1 cm, G2= 1-2 cm, G3> 3 cm). USE evaluation comprised the measurement of the percentage of the areas included in the region of interest corresponding to the maximal stiffness (% Index) and of the SI. Results: The % Index and of the SI were significantly higher in malignant than in benign thyroid nodules, and both measurements displayed a good diagnostic performance (SI sensitivity and specificity = 0.66 and 0.90, respectively; % index sensitivity and specificity = 0.76 and 0.89, respectively). Compared with SI, the % Index was more informative, both in the whole group of thyroid nodules (OR[95%CI]=18.68[6.06-63.49], p=1.49x10-8, vs OR[95%CI]=26.15[8.01-102.87], p=3.41x10-10 respectively) and in the G1 and G2 subgroups. Conclusion: The % Index is a stronger predictor of nodule malignancy than both the SI and the conventional US signs. This is particularly true in nodules smaller than 1 cm, which are more difficult to be explored both by conventional US and by FNAC.
Key words: thyroid, real time elastography, thyroid nodule, thyroid cancer Word Count: Text 2667
DOI:10.4158/EP14504.OR © 2014 AACE.
Abbreviations: US = Ultrasound, USE = Ultrasound elastography, SI = Strain index, FNAC = Fine needle aspiration cytology, % Index = Percentage of maximal stiffness within the nodule, ATA = American Thyroid Association, MCC = Mattew’s Correlation Coefficient, AUROC = Area Under the ROC Curve, OR = Odds ratio, PPV = positive predictive value, NPV = negative predictive value, RTE = Real time elastography.
Introduction Thyroid nodules affect up to 50% of people living in iodine deficient areas [1], and are more common in females than in males (F:M ratio=4:1) . Thyroid nodules are often incidentally discovered by palpation and more frequently by thyroid ultrasound (US), their incidence increases in relation to age, previous neck irradiation and some clinical conditions such as acromegaly [2-4]. The differential diagnosis between benign and malignant thyroid nodules is crucial due to their high prevalence in the general population and the increasing incidence of thyroid cancer observed in the last 20 years [5-7]. Fine-needle aspiration cytology (FNAC) is the gold standard in the differential diagnosis of thyroid nodules [1]. FNAC is a highly specific and sensitive tool, but it is also an expensive and minimally invasive procedure. Conventional US is usually employed in the first step evaluation of thyroid nodules. Five US features of thyroid nodules (hypo-echogenicity, irregular margins, micro-calcifications, increased vascularization, and regional lymphadenopathy) are well known predictors of malignancy. [8-10].
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However none of them, by itself or in combination, has an adequate sensitivity or specificity [1114]. Because a hard consistency of the nodule is usually associated with an increased risk of malignancy, ultrasound elastography (USE) was recently introduced in the diagnostic work up of thyroid nodules. The latest American Thyroid Association (ATA) Guidelines mentioned elastography as a promising technique, still requiring validation [11]. Several studies showed that USE can detect thyroid malignancy with high sensitivity and specificity even in case of indeterminate or non diagnostic cytology [15-21], although other reports challenged these findings [22,23]. Using a qualitative (elasticity score) or a semi-quantitative approach, the Strain index (SI), USE was reported to be able of predicting thyroid malignancy [15-18]. However, real time techniques suffer from several limitations mainly represented by their operator dependency, the presence of calcifications or cystic fluid within the nodule, the nodule size and the position within the gland. Interfering effects from carotid artery pulsation may also hamper the procedure [16,24,25]. Despite these limitations, we previously demonstrated that the SI owns an excellent diagnostic performance in predicting thyroid malignancy, which was higher than that provided by any conventional US sign [15]. Aim of the present study was: i) to evaluate, as compared with the SI, the diagnostic performance of a new USE parameter based on the measurement of the percentage of maximal stiffness within the nodule, and ii) to investigate whether nodule size could affect the diagnostic accuracy of these two USE measurements.
Subjects and methods The recruitment of cases was carried out from December 2013 to February 2014, and involved the examination of 250 consecutive patients harbouring one or more thyroid nodules. The total number DOI:10.4158/EP14504.OR © 2014 AACE.
of evaluated nodules was 296. Data concerning family and personal history were recorded. The serum levels of TSH, FT4, FT3, calcitonin, anti-thyroglobulin and anti-thyroid-peroxidase antibodies were also measured. Before FNAC, a conventional US and the USE evaluation were performed. Exclusion criteria for USE were pure cystic lesions, insufficient normal tissue around the target nodule, the occurrence of isthmic and para-isthmic nodules due to the interference produced by the tracheal cartilage. Two hundred and twelve patients (median age = 57 yrs., 25th and 75th percentile = 44-66 yrs.) fulfilled the inclusion criteria. A total of 243 thyroid nodules were evaluated for the study. All patients gave their written informed consent to participate in the study and to allow the future use of their clinical data for research purposes according to the local ethics committee and the guidelines of the Declaration of Helsinki. As previously described [15], thyroid US evaluation was performed using a real-time US device equipped with a linear transducer operating at 7.5 MHz (Mylab 70XVG). Thyroid nodules were carefully examined for the following US features: nature, i.e. solid, cystic or mixed; echogenicity, i.e. hyperechoic, isoechoic or hypoechoic compared with normal parenchyma and with neck muscles; size; homogeneity, i.e. homogeneous or inhomogeneous; micro-calcifications (hyper-echoic spots < 2 mm without acoustic shadowing); presence of regular or irregular margins; halo sign, i.e. presence or absence of an hypoechoic rim; color-flow Doppler pattern. The nodule volume was calculated by the elliptical shape volume formula (length x width x depth x 0.479). All thyroid US scans were performed by the same operator (S.C.), who had a more than 5-year experience with thyroid imaging. The same US device was used to perform USE, according to the technique described by Cakir et al [26] (see for detail [15] ). Briefly, the operator, after having achieved the optimal level of compression, used an electronic box, which included the selected nodule and a sufficient amount of surrounding parenchyma. Within this box the operator identified two regions of interest: the first one corresponding to the nodule and the second one corresponding to the softest area of normal DOI:10.4158/EP14504.OR © 2014 AACE.
parenchyma, identified by its red color on elastosonogram. The SI was calculated as the ratio of thyroid nodule strain over the strain of the softest area of parenchyma. In the present study the software employed for calculating the SI was improved by allowing the measurement of the percentage of all areas included in the region of interest (nodule), which had the maximal stiffness (namely the percentage of pure blue colour within the nodule). This measurement was defined as the percent Index (% Index). Fig. 1 shows the elastographyc strain index and % Index in a benign (panel A) and a malignant (panel B) thyroid nodule. FNAC was performed according to the current guidelines [27] under US guidance by a skilled endocrinologist using a 23-gauge needle attached to a 2.5 ml syringe. Cytological samples were classified into 6 classes [28]: non-diagnostic (THY 1, no. = 16; accounting for 6.6%), which were excluded from the study; benign (THY2, no. = 193; 79.5%); indeterminate follicular lesion (THY3a and THY3b, no. = 15; 6.1%), suspicious for malignancy (THY4 no. = 5; 2.1%); malignant (THY5, no. = 14; 5.7%). Nine of the 15 THY3 nodules were excluded from the study due to the lack of corresponding histologic data, while 6 (THY3a = 3 and THY3b = 3) were included in the study. At histology, 2 malignant lesions and 4 follicular adenomas were diagnosed among the 6 THY3 operated nodules. All nodules with a THY4 or THY5 cytology were confirmed as malignant lesions by histology on surgical specimens. The final study group included 218 thyroid nodules. Thyroid nodules were further stratified according to their size: G1 < 1 cm, G2 = 1-2 cm, G3 > 3 cm. Benign thyroid nodules, as assessed by FNAC, were submitted to a follow-up observation consisting in periodical physical examination and conventional US and USE evaluation. The time interval between subsequent controls ranged from 6 to 12 months. FNAC was repeated in case of increased size, as indicated in the ATA guidelines [11,27], or of changes in US or USE features. Until now, no change in the diagnosis of benign nodule occurred.
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Statistical analysis Since most of the quantitative variables deviated significantly from normality (Shapiro-Wilk p < 0.05), all distributions were described as median (25th – 75th percentiles) and non-parametric tests were applied. The Wilcoxon Rank-Sum test for paired samples was applied to test for statistically significant differences in terms of distribution of quantitative variables between two experimental conditions. The Spearman test was applied to evaluate the correlation between quantitative variables. The Fisher’s Exact test was used to evaluate the association between categorical variables. Stepwise logistic regression was used to identify the most informative variable being relevant for the diagnosis of thyroid nodules. The best cut-off values for the % Index and the SI in discriminating malignant from benign nodules were estimated by the following resampling procedure repeated 1,000 times: - On each training set: Record the values that the variable may assume. - On the corresponding test set: Estimate and record the predictive accuracy (expressed in terms of Mattew’s Correlation Coefficient - MCC) of each value observed in the training set. The most informative cut-off was estimated by taking the values of % Index or SI, which reached the maximum median MCC over the 1,000 re-samplings. Statistical analyses were performed by the R software v3.0.2 (www.r-project.org/).
Results Diagnostic performance of USE strain index and % index Table I summarizes the clinical data, the conventional US signs and the USE findings, expressed as % Index and SI, of the 218 thyroid nodules included in the study. Malignant nodules had a significantly higher prevalence of three US signs of malignancy (hypo-echogenicity, irregular borders and micro-calcifications). Although not significant, a smaller volume of the nodule was also DOI:10.4158/EP14504.OR © 2014 AACE.
associated with malignancy. When the maximum diameter was considered, nodules larger than 1 cm (i.e. belonging to the G2 and G3 subgroups) had a statistically significant lower risk of being malignant with respect to those belonging to the G1 subgroup (OR = 0.175, 95 % CI = 0.056 – 0.553, p = 0.002 and OR = 0.238, 95 % CI = 0.062 – 0.853, p = 0.029 for G2 and G3 respectively). Moreover, nodules smaller than 1 cm in diameter had a 5-fold increased risk of being malignant with respect to those with a diameter greater than 1 cm (OR = 5.17, 95% CI = 1.737 – 14.598, p = 0.002). With specific regard to USE evaluation, the median values of both % Index and SI were significantly higher in malignant than in benign thyroid nodules. The values of the % Index and of the SI were strongly correlated (r = 0.87, p< 3x10-6) between each other. As shown in Fig 2a , the Area Under the ROC Curve (AUROC) estimates corresponding to the two USE parameters were also very similar. When the % Index and the SI were analyzed in relation to the nodule size, both parameters were strongly predictive of malignancy in thyroid nodules larger than 1 cm (G2 and G3 subgroups), but not in smaller thyroid nodules (G1 subgroup) (Fig. 2b and 2c). Identification and evaluation of the USE strain index and % index cut-off The identification of cut-off values for the % Index and the SI was performed by a resampling procedure repeated 1000 times, as described in the statistical analysis section. The most informative cut-off values discriminating benign from malignant thyroid nodules were 57.6 and 4.24 for % Index and SI, respectively (Fig. 3). The diagnostic performance of the cut-off values of the % Index and of the SI was then tested both in the whole study group of thyroid nodules and in the subgroups stratified according to the nodule size (G1, G2 and G3). Results were expressed in terms of Mattew’s Correlation Coefficient (MCC), Area Under the ROC Curve (AUROC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and F-Measure. As summarized in Table II, both the % Index and the SI cut-offs were highly informative for predicting nodule malignancy. In particular, when compared with the SI cut-off, the % Index cut-off reached DOI:10.4158/EP14504.OR © 2014 AACE.
slightly higher discriminative performances in the whole study group and in the G1 and G2 subgroups, being superimposable in the G3 subgroup. Univariate association tests showed that the % Index cut-off > 57.6 was the USE parameter with the strongest impact on the risk of malignancy when compared with the SI cut-off > 4.24 (OR [95%CI] = 26.15 [8.01-102.87], p=3.41 x 10-10 vs OR [95%CI] = 18.68 [6.06-63.49], p=1.49 x 10-8, respectively). As shown in Table III, stepwise logistic regression starting from a full model represented by the complete set of covariates reported in table I revealed that % Index cut-off, age, irregular margins, micro-calcifications are the most informative predictors of the risk of thyroid malignancy. These statistics also suggest that the % index cut-off is more informative than the SI cut-off even when other predictors are taken into account in a multivariate approach. Discussion In this study we evaluated the diagnostic performance of a new USE parameter based on the measurement of the percentage of maximal stiffness within a nodule (defined as % Index) with the already established elastographic strain index (SI). As recently shown by our group, the SI displays a high sensitivity, specificity and negative predictive value for the diagnosis of thyroid malignancy [15]. These data were confirmed in the present study. The % Index, obtained using a different software, but during the same procedure as SI, evaluates the percentage of the area with a maximal stiffness within a nodule. The two elastographic measurements were found to be strongly correlated between each other. However, the % Index, when compared with the SI, was more informative. This is probably because the % Index highlights the hardest parts of the region of interest, while the SI considers the mean stiffness of the nodule. To the best of our knowledge, the present study is the first one validating the % index as a reliable tool in the differential diagnosis of thyroid nodules. Indeed, the median % Index was significantly higher in malignant than in benign nodules. Moreover, when compared with the SI and with conventional DOI:10.4158/EP14504.OR © 2014 AACE.
US signs in a multivariate analysis, the % Index was a significantly stronger predictor of malignancy. Compelling evidence indicates that nodule size, although considered by most current guidelines a criterion for selecting nodules to be biopsied, is not a reliable predictor of malignancy [11,17]. Moreover, papillary micro-carcinomas encompass all sorts of histotypes, including the poorly circumscribed and/or the infiltrative ones [29]. Micro-carcinomas may not exhibit obvious changes in morphology and are difficult to be recognized by conventional US [30]. Previous studies using USE in the differential diagnosis of small thyroid nodules also gave conflicting results. Cappelli et al. suggested that real time elastography (RTE) is a useful tool even in small (3-10 mm of maximum diameter) thyroid nodules, having a sensitivity of 91% and a specificity of 89% [31]. By applying the same procedure to a surgical series of patients with single thyroid nodules smaller than 10 mm, Wang et al. found a sensitivity of 90.6%, a specificity of 89.5% and an accuracy of 90.2 %. The positive and negative predictive values were 93.5 % and 85.0 %, respectively [30]. Less promising results were reported by Liu et al. in a study comparing the diagnostic performance of shear wave elastography (SWE) and RTE in nodules of different size. In this study, RTE had a low sensitivity (88.9 %) and specificity (70.0 %) in nodules smaller than 1 cm; the diagnostic performance of SWE was even poorer, with a sensitivity of 44.4% and a specificity of 90% [32]. In the present study, the discriminating capability of both the % Index and the SI was evaluated in nodules stratified according to their increasing size. In thyroid nodules smaller than 1 cm, the % Index was found to be the most accurate predictor of malignancy. Thus, the % index is a reliable adjunctive diagnostic tool for identifying malignant thyroid nodules. However, it still suffers from several limitations, which are shared by other USE techniques: operator dependency, interfering effects produced by calcifications or cystic fluids within the nodule, nodule size and position within the gland, and carotid artery pulsation [24]. In the present DOI:10.4158/EP14504.OR © 2014 AACE.
study we excluded 53 thyroid nodules (17.8% of the initial sample) from USE evaluation. Despite this limitation, the semi-quantitative elastographic approach, based on the evaluation of the SI and of the percentage of all areas included in the nodule with the maximal stiffness (% Index), allowed to better standardize the procedure with a reduction of the inter-observer variability, as well as of the variability in data acquisition, which often limits the results of the elastographic evaluation. The great number of papers addressing this issue demonstrates its relevance [33-35]. In conclusion, the percentage of the area included in the region of interest (nodule) corresponding to the maximal stiffness (% index) is a useful parameter to be used in the differential diagnosis of thyroid nodules and for selecting the ones to be submitted to FNAC. Multi-center prospective studies are needed to validate our results in a larger population. If our data were confirmed, the % Index might be considered as an adjunctive diagnostic tool to conventional US in the setting of diagnostic thyroid nodule management.
Conflict of Interest: There were no grants or fellowship support in writing of this manuscript. The authors have no conflict of interest regarding the publication of this article.
DOI:10.4158/EP14504.OR © 2014 AACE.
REFERENCES 1.
Hegedus L. Clinical practice. The thyroid nodule. N Engl J Med 2004;351:1764-1771
2.
Dean DS, Gharib H. Epidemiology of thyroid nodules. Best Pract Res Clin Endocrinol Metab 2008;22:901-911
3.
Malboosbaf R, Hosseinpanah F, Mojarrad M, Jambarsang S, Azizi F. Relationship between goiter and gender: a systematic review and meta-analysis. Endocrine 2013;43:539547
4.
Guo H, Sun M, He W, et al. The prevalence of thyroid nodules and its relationship with metabolic parameters in a Chinese community-based population aged over 40 years. Endocrine 2014;45:230-235
5.
Enewold L, Zhu K, Ron E, et al. Rising thyroid cancer incidence in the United States by demographic and tumor characteristics, 1980-2005. Cancer Epidemiol Biomarkers Prev 2009;18:784-791
6.
Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913-2921
7.
Davies L, Welch HG. Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg 2014;140:317-322
8.
Moon HJ, Sung JM, Kim EK, et al. Diagnostic performance of gray-scale US and elastography in solid thyroid nodules. Radiology 2012;262:1002-1013
9.
Asteria C, Giovanardi A, Pizzocaro A, et al. US-elastography in the differential diagnosis of benign and malignant thyroid nodules. Thyroid 2008;18:523-531
10.
Khoo ML, Asa SL, Witterick IJ, Freeman JL. Thyroid calcification and its association with thyroid carcinoma. Head Neck 2002;24:651-655
DOI:10.4158/EP14504.OR © 2014 AACE.
11.
Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19:1167-1214
12.
Rago T, Vitti P. Diagnostic role of ultrasound and elastosonography in nodular goiter. Best Pract Res Clin Endocrinol Metab 2014;28:519-529
13.
Rago T, Vitti P, Chiovato L, et al. Role of conventional ultrasonography and color flowdoppler sonography in predicting malignancy in 'cold' thyroid nodules. Eur J Endocrinol 1998;138:41-46
14.
Gharib H, Papini E, Paschke R, et al. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. J Endocrinol Invest 2010;33:51-56
15.
Magri F, Chytiris S, Capelli V, et al. Comparison of elastographic strain index and thyroid fine-needle aspiration cytology in 631 thyroid nodules. J Clin Endocrinol Metab 2013;98:4790-4797
16.
Grazhdani H, Cantisani V, Lodise P, et al. Prospective evaluation of acoustic radiation force impulse technology in the differentiation of thyroid nodules: accuracy and interobserver variability assessment. J Ultrasound 2014;17:13-20
17.
Bojunga J, Herrmann E, Meyer G, et al. Real-time elastography for the differentiation of benign and malignant thyroid nodules: a meta-analysis. Thyroid 2010;20:1145-1150
18.
Rago T, Santini F, Scutari M, Pinchera A, Vitti P. Elastography: new developments in ultrasound for predicting malignancy in thyroid nodules. J Clin Endocrinol Metab 2007;92:2917-2922
DOI:10.4158/EP14504.OR © 2014 AACE.
19.
Rago T, Vitti P. Role of thyroid ultrasound in the diagnostic evaluation of thyroid nodules. Best Pract Res Clin Endocrinol Metab 2008;22:913-928
20.
Magri F, Chytiris S, Capelli V, et al. Shear wave elastography in the diagnosis of thyroid nodules: feasibility in the case of coexistent chronic autoimmune Hashimoto's thyroiditis. Clin Endocrinol (Oxf) 2012;76:137-141
21.
Rago T, Scutari M, Santini F, et al. Real-time elastosonography: useful tool for refining the presurgical diagnosis in thyroid nodules with indeterminate or nondiagnostic cytology. J Clin Endocrinol Metab 2010;95:5274-5280
22.
Unlütürk U, Erdoğan MF, Demir O, Güllü S, Başkal N. Ultrasound elastography is not superior to grayscale ultrasound in predicting malignancy in thyroid nodules. Thyroid 2012;22:1031-1038
23.
Kim H, Kim JA, Son EJ, Youk JH. Quantitative assessment of shear-wave ultrasound elastography in thyroid nodules: diagnostic performance for predicting malignancy. Eur Radiol 2013;23:2532-2537
24.
Cantisani V, Lodise P, Grazhdani H, et al. Ultrasound elastography in the evaluation of thyroid pathology. Current status. Eur J Radiol 2014;83:420-428
25.
Cantisani V, Lodise P, Di Rocco G, et al. Diagnostic Accuracy and Interobserver Agreement of Quasistatic Ultrasound Elastography in the Diagnosis of Thyroid Nodules. Ultraschall Med 2014
26.
Cakir B, Aydin C, Korukluoğlu B, et al. Diagnostic value of elastosonographically determined strain index in the differential diagnosis of benign and malignant thyroid nodules. Endocrine 2011;39:89-98
27.
Gharib H, Papini E, Paschke R, et al. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association Medical guidelines
DOI:10.4158/EP14504.OR © 2014 AACE.
for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. Endocr Pract 2010;16:468-475 28.
London RCoPo. Guidelines for the management of thyroid cancer. In: The Lavenham Press, Suffolk, 2nd ed.; 2007
29.
Soares P, Celestino R, Gaspar da Rocha A, Sobrinho-Simões M. Papillary thyroid microcarcinoma: how to diagnose and manage this epidemic? Int J Surg Pathol 2014;22:113-119
30.
Wang Y, Dan HJ, Dan HY, Li T, Hu B. Differential diagnosis of small single solid thyroid nodules using real-time ultrasound elastography. J Int Med Res 2010;38:466-472
31.
Cappelli C, Pirola I, Gandossi E, et al. Real-time elastography: a useful tool for predicting malignancy in thyroid nodules with nondiagnostic cytologic findings. J Ultrasound Med 2012;31:1777-1782
32.
Liu BX, Xie XY, Liang JY, et al. Shear wave elastography versus real-time elastography on evaluation thyroid nodules: a preliminary study. Eur J Radiol 2014;83:1135-1143
33.
Cantisani V, Grazhdani H, Ricci P, et al. Q-elastosonography of solid thyroid nodules: assessment of diagnostic efficacy and interobserver variability in a large patient cohort. Eur Radiol 2014;24:143-150
34.
Calvete AC, Rodríguez JM, de Dios Berná-Mestre J, et al. Interobserver agreement for thyroid elastography: value of the quality factor. J Ultrasound Med 2013;32:495-504
35.
Ragazzoni F, Deandrea M, Mormile A, et al. High diagnostic accuracy and interobserver reliability of real-time elastography in the evaluation of thyroid nodules. Ultrasound Med Biol 2012;38:1154-1162
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Table I. Clinical data, conventional US signs of malignancy and USE strain index and % index values of patients with benign and malignant thyroid nodules. Data are expressed as median (interquartile range) or as percent
Thyroid nodules Malignant (n = 21) Benign (n = 197) Age (y) Gender (males) Strain Index (S.I.) % Index
p
50 (45, 60)
57 (44, 66.75)
0.078
4 (19.05)
45 (22.9)
0.789
5.36 (3.17, 6.12)
2.63 (2.11, 3.27) < 1 x 10 – 5
75.03 (57.69, 91.20)16.53 (6.13, 34.10) < 1 x 10 – 6
Hypo-ecogenicity (yes)
16 (76.19)
77 (39.4)
0.002
Irregular borders (yes)
8 (38.01)
1 (0.5)
< 1 x 10 – 6
Micro-calcifications (yes)
10 (47.62)
15 (7.6)
1.35 x 10 – 5
Vascularization (yes)
9 (42.86)
51 (25.8)
0.122
Volume (ml)
0.71 (0.34, 1.63)
0.85 (0.50, 2.13)
0.188
Max Diameter
1.21 (0.96, 1.86)
1.50 (1.23, 2.07)
0.050
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Table II. Diagnostic performance of USE SI and % index cut-offs in the whole study group and within the subgroups obtained on the basis of the nodule size (G1, G2 and G3). % Index ≥ 57.60 Group Whole G1 G2 G3
MCC 0.536 0.162 0.601 0.778
AUROC 0.828 0.581 0.941 0.889
Group MCC AUROC Whole 0.492 0.786 G1 -0.048 0.476 G2 0.589 0.899 G3 0.778 0.889
Sensitivity 0.762 0.429 1.000 0.800
Specificity 0.894 0.733 0.882 0.978
PPV 0.471 0.429 0.409 0.800
NPV 0.968 0.733 1.000 0.978
F-Measure 0.582 0.429 0.581 0.800
Strain Index ≥ 4.24 Sensitivity Specificity 0.667 0.906 0.286 0.667 0.889 0.909 0.800 0.978
PPV 0.467 0.286 0.444 0.800
NPV 0.957 0.667 0.990 0.978
F-Measure 0.549 0.286 0.593 0.800
MCC = Mattew’s Correlation Coefficient; AUROC = Area Under the ROC Curve; PPV = positive predictive value; NPV = negative predictive value
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Table III. Stepwise logistic regression including clinical, conventional US and USE parameters associated to thyroid malignancy
OR
L95
Age (y)
0.948
0.896 0.995
% Index ≥ 57.60
21.307 5.800 96.783
Irregular margins
47.125 5.037 1184.660 0.003
Micro-calcifications 8.534
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U95
1.820 44.552
p 0.040 1.33 x 10-5
0.007
Fig. 1 Examples of elastographyc strain index and % index measurements in benign (panel A) and malignant (panel B) thyroid nodule
A
B
Fig. 2. ROC curves corresponding to the SI and % index evaluation (continuous variables) in the whole study group (a) and in the three subgroups obtained according to nodule size (b)
a
b
Fig. 3. Identification of the USE SI and % index cut-off by resampling procedure repeated 1000times (Mathew’s Correlation Coefficient - MCC).
Dark continuous line=median p ) Blue line= 25th and 75th percentiles) Grey dotted line= range non outliner
