- Email: [email protected]
The diagnostic value of combination of TI-RADS and ultrasound elastography in the differentiation of benign and malignant thyroid nodules
Clinical Imaging 40 (2016) 913–916
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: http://www.clinicalimaging.org
The diagnostic value of combination of TI-RADS and ultrasound elastography in the differentiation of benign and malignant thyroid nodules Jie Xue a,1, Xiao-li Cao a,1, Lei Shi a, Chun-hua Lin b, Jiahui Wang c, Lihong Wang a,⁎ a b c
Ultrasonic Department, Yantai Yuhuangding Hospital, Yantai, Shandong, 264000, China Urology Department, Yantai Yuhuangding Hospital, Yantai, Shandong, 264000, China Central Laboratory, Yantai Yuhuangding Hospital, Yantai, Shandong, 264000, China
a r t i c l e
i n f o
Article history: Received 17 March 2016 Received in revised form 19 April 2016 Accepted 27 April 2016 Available online xxxx Keywords: Thyroid imaging reporting and data system, TI-RADS Elasticity imaging techniques Thyroid nodule Ultrasonography
a b s t r a c t Background: Here, we evaluated the diagnostic value of combination of thyroid imaging-reporting and data system (TI-RADS) and ultrasound elastography (USE) in risk assessment of thyroid nodules. Methods: The clinical data of 174 patients with 232 nodules were retrospectively analyzed. All nodules were examined by gray-scale ultrasonography and USE and confirmed by histological examination. Results: The sensitivity, specificity, and accuracy of the combination of the two methods were significantly higher than those using a single method. Conclusion: The combination of TI-RADS and USE has high diagnostic sensitivity and accuracy in evaluating the malignant risk of thyroid nodules.
© 2016 Elsevier Inc. All rights reserved.
1. Background Ultrasonography is currently the major approach in the diagnosis of thyroid nodules. However the accuracy of ultrasonography is relatively low in differentiating benign and malignant thyroid nodules [1]. Fine needle aspiration (FNA) could be used as a supplement in evaluating the risk of thyroid nodules ≧10 mm. However, despite its high specificity of 60%–98%, the diagnostic sensitivity of FNA could be as low as 65–68% [2]. Many patients underwent operation without a definite qualitative diagnosis, which placed extra physical, psychological, and economic burdens to the patients. To avoid unnecessary biopsy and operation, the thyroid imaging-reporting and data system (TI-RADS) was developed by Parker et al. for risk stratification of thyroid nodules [3]. However, TI-RADS has been limited in clinical application and questioned for its feasibility and practicability due to the practice being too subjective. In recent years, ultrasound elastography (USE) has been increasingly used in the risk assessment of thyroid nodules. A meta-analysis reported 92% overall mean sensitivity and 90% specificity for the diagnosis of malignant thyroid nodules by USE, respectively [4]. In this study, we investigated and discussed the clinical value of
⁎ Corresponding author. Yantai Yuhuangding Hospital, 20 Yuhuangding East Road, Yantai, Shandong, 264000, China. Tel.: +86-535-6691999. E-mail address: [email protected] (L. Wang). 1 Equal contribution. http://dx.doi.org/10.1016/j.clinimag.2016.04.014 0899-7071/© 2016 Elsevier Inc. All rights reserved.
the combination of TI-RADS and USE in the differential diagnosis of benign and malignant thyroid nodules. 2. Material and methods 2.1. Patients In this retrospective study, 232 nodules in 174 consecutive patients (72 male, 102 female, aged 25–58 years old, median age 43.4) admitted to Yantai Yuhuangding Hospital between September 2011 and December 2013 were examined. The inclusion criteria were patients with solid or cystic-solid mixed nodules that were ≧5 mm, without “egg-shell” calcification on the edge, and surrounding thyroid tissues were normal. For multiple nodules, the large ones or those with malignant probability were chosen. All nodules were examined by gray-scale ultrasonography and USE examinations, and final diagnoses were obtained from pathological evaluation. The maximum diameters of nodules ranged from 7 to 24 mm. This study was approved by the Ethics Committee of Yantai Yuhuangding Hospital. Written informed consents were obtained from patients before all examinations and treatments for the inclusion of clinical data for scientific research and publication purpose. 2.2. Imaging techniques US examinations for all patients were performed by the same physician.
914
J. Xue et al. / Clinical Imaging 40 (2016) 913–916
Ultrasonography was performed using two ultrasound systems (LogicE9, GE Healthcare, Milwaukee, WI, USA; Aplio™ 500, Toshiba Medical Systems Co. Ltd., Otawara, Japan). Patients took the spine position with adequate exposure of the neck. The thyroid was scanned from the anterior aspect of the neck at different angles (transverse, sagittal, and oblique). Information of the nodules including their location, number, size, shape, boundary, aspect ratio (the ratio of the longitudinal against the axial length), internal echo, ultrasound attenuation and microcalcification as well as any enlargement of cervical lymph nodes were recorded. Extra attention was paid to the lymph nodes at area 3, 4, 6, and 5 (5 A and 5B) of bilateral neck. The characteristics of thyroid nodules were valuated with two-dimensional gray-scale ultrasonography. For USE examination, the sampling frame of the region of interest (ROI) included the nodules and the surrounding normal thyroid tissue. The probe made slight vibrations upon the nodules at a frequency of twice per second and a depth of pressure of 1–2 mm until it reached the optimal pressure and frequency, which showed all green in the indicator shaft for Logic E9 or regular waveform curves for Aplio 500 scanner. The gray-scale images and elastograms were real-time displayed and monitored simultaneously. The elasticity of diverse tissues was represented by different colors in the elasotogram. Green represented the average tissue hardness within the ROI. Red indicated softer tissues than the average, and blue suggested harder tissues. The color distribution of each nodule was recorded and classified. 2.3. Scoring system Retrospective investigation was done by Medical Picture Archiving and Communication System (Medicon Digital Engineering Co. LTD, Qingdao, China). All ultrasonic images were independently evaluated by two physicians with at least five years of ultrasound work experience. In case of disagreement, the image was evaluated by a third associate chief physician with more than seven years of ultrasound work experience until consensus was reached upon discussion. The thyroid nodules were scored according to the TI-RADS scoring system [5]: TI-RADS 1 (Score 1): normal thyroid or diffuse hyperplasia of thyroid. TI-RADS 2 (Score 2): benign conditions, mainly included the glial Type I, II and III nodules. TI-RADS 3 (Score 3): probably benign nodules, mostly seen in the Hashimoto's thyroiditis. TI-RADS 4 A (Score 4): indeterminate nodules (malignancy between 5 and 10%), including solid iso-echoic nodules or mix-echoic nodules coated in capsules; hypoechoic nodules with unclear boundaries and no calcification; calcified nodules coated in thick capsules and with rich blood supply. TI-RADS 4B (Score 5): suspicious nodules (malignancy between 10 and 80%), which are hypochoic, no capsule, with irregular form and boundaries, with perforator blood vessels and with/without calcification. TI-RADS 5 (Score 6): probably malignant nodules, which are isoechoic or hypochoic, no capsule, with rich blood supply and microcalcification. Score 1–3 were classified as benign and 4–6 as malignant. We also scored the nodules using the USE scoring system by Asteria et al. [6] and Rubaltelli et al. [7]: Score 1: elasticity in the whole examined area (all green). Score 2: elasticity in a large part of the examined area (majority of the nodule area was green with a little blue area). Score 3: stiffness in a large part of the examined area (majority of the nodule area was blue with a little green area). Score 4: a nodule without elasticity (all blue). Score 1–2 were classified as benign and 3–4 as malignant.
For combined TI-RADS/USE diagnosis, the TI-RADS score and USE score of each nodule were added. A final score of 2–6 were considered benign nodules and 7–10 were malignant nodules. Pathological results were used as a golden standard for evaluating the diagnosis value of TI-RADS/USE combined system in risk assessment of thyroid nodules. 2.4. Pathological diagnosis Tissue samples of each nodule were obtained from operation or ultrasound-guided core biopsy. Surgically resected nodules were subjected to intra-operative frozen section for preliminary risk assessment. Final diagnosis was based on postoperative paraffin section pathological examinations. Nodule tissues obtained from biopsy were fixed in paraformaldehyde and subjected to paraffin section pathological examinations. In case of suspicious malignant samples or atypical samples, immunohistochemical staining was applied to differentiate benign and malignant nodules. If biopsy suggested follicular carcinoma, the whole tumor was surgically removed for definite diagnosis. Benign nodules mainly comprised nodular goiter, glial nodules, adenoma, and Hashimoto's thyroiditis. Malignant nodules were mainly papillary carcinoma, in less case follicular and medullary carcinoma, and occasionally thyroid lymphoma. 2.5. Statistics Statistical analysis was performed using the Statistical Product and Service Solutions 17.0 software. The diagnostic efficacy of USE and TIRADS were compared by sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) using χ2-test. Receiver operating characteristic curve (ROC) was plotted, and area under the curve (AUC) was calculated. Z-test was utilized to compare the AUC of ROC. Pb .05 indicated statistically significant difference. 3. Results The diagnosis of the 232 nodules by TI-RADS scoring, USE scoring, combined TI-RADS/USE scoring, and pathological diagnoses was summarized in Table 1. Pathological tests showed that 160 were benign and 72 were malignant (69 papillary carcinomas, 3 follicular carcinomas). Based on the TI-RADS score, 153 nodules were benign (92 nodules scored 2, 61 scored 3), and 79 were malignant (52 scored 4 or 5 points, 27 scored 6). Based on the USE scores, there were 153 benign nodules (53 nodules scored 1, 102 scored 2) and 77 malignant nodules (32 nodules scored 3, 45 scored 4). Based on combined TI-RADS/USE scores, there were 155 benign nodules and 77 malignant nodules (Fig. 1). Our result showed that both the sensitivity and accuracy of USE evaluation system were significantly higher than the TI-RADS system alone (χ 2 =3.920, 7.446. P b .05). In case of combined TI-RADS/USE scoring, there was a significant improvement in the sensitivity, specificity, and accuracy of diagnosis than TI-RADS (χ2 =7.725, 6.450, 13.728. P b.05) (Table 2). The ROC of TI-RADS, USE, and combined TI-RADS/USE analysis were individually plotted (Fig. 2), and their AUC were calculated. Result showed that the AUC for TI-RADS diagnosis system was 0.812 with standard error 0.032, 95% confidence interval (CI)=0.749–0.874. The AUC for USE diagnosis system was 0.833; standard error, 0.034; 95% CI=0.767–0.899. The AUC for combined TI-RADS/USE diagnosis system Table 1 The number of nodules in each diagnostic group based on the TI-RADS, USE, and combined TI-RADS/USE scoring system Pathological classification
TI-RADS
Benign Malignant
136 17
USE
TI-RADS/USE
Benign Malignant Benign Malignant Benign Malignant 24 55
147 8
13 64
150 5
10 67
J. Xue et al. / Clinical Imaging 40 (2016) 913–916
915
Fig. 1. A 56-year-old female patient with papillary thyroid carcinoma. (A) Gray-scale ultrasonography showed a hypoechoic nodule in the right thyroid lobe with maximum diameter N10 mm, unclear boundary, uneven internal echo, and no calcification foci. It scored 3 points in TI-RADS system, suggesting possible benign nodule. (B) USE showed stiffness in a large part of the nodule area and scored 3 points, suggesting malignant nodule. (C) Hematoxylin-Eosin staining of the pathological section, visualized under microscope at ×100. Result showed follicular epithelial papillary hyperplasia infiltrating to surrounding tissues. Nuclei of glass appearance, nuclear grooves, and intranuclear pseudoinclusions were observed. Cell nuclei were enlarged and lightly colored.
was 0.914; standard error, 0.024; 95% CI=0.868–0.960. There was no significant difference between the AUC of TI-RADS and USE (Z=0.45, PN.05). The AUC for combined TI-RADS/USE was significantly different from that of USE or TI-RADS (Z=1.95 and 2.55, Pb.05). 4. Discussion A thyroid nodule is the most common thyroid diseases and epidemiologic studies have revealed an increasing morbidity each year [8]. It has become a research hotspot to increase the diagnostic accuracy for differentiation between benign and malignant thyroid nodules. Ultrasonography is able to not only differentiate solid nodules to cystic nodules but also facilitate the differential diagnosis of benign and malignant nodules based on the ultrasonic characteristics including the location, form, size, echo, calcification, echo halo, boundary, and internal blood flow of the nodules. There is no single ultrasound feature that can provide enough accuracy in the differential diagnosis of benign and malignant thyroid nodules. The combination of multiple ultrasound features will greatly improve the diagnostic sensitivity and specificity. Therefore Park et al. proposed the TI-RADS system to predict the probability of malignancy in thyroid nodules based on the features of thyroid nodules as noted on ultrasound [3]. In this study, the TI-RADS scoring system achieved a sensitivity of 76.4%, specificity 85.0%, accuracy 82.3%, PPV 69.6%, and NPV 88.9%. Our specificity was lower than reported by Horvath et al., which is 88% [5], suggesting misdiagnosis of malignant nodules. This was probably due to that thyroid tumors, inflammation or hyperplasia caused overlaps in ultrasound features, interfering the subjective judgment of observer. In this study, 12 pathologically confirmed malignant nodules were false diagnosed as benign by the TI-RADS system (scored 3 points). Among them 9 nodules were diagnosed correctly by the USE system (scored N2). Our study showed that 5 of the false-negative nodules were thyroid microcarcinoma with a maximum diameter of b10 mm. The gray-scale ultrasonography for thyroid microcarcinoma features low echo-level, no acoustic halo, microcalcification, no cystic degeneration, and others [9], none of which is the specific symptom of diagnosing thyroid microcarcinoma. Therefore, it is likely to be confused with or masked by the acoustic phase of nodular goiter. In this study, the
Table 2 Comparison of the diagnostic efficacy among the TI-RADS, USE, and combined TI-RADS/ USE evaluation system (%) Evaluation method
Sensitivity
Specificity
Accuracy
PPV
NPV
TI-RADS USE TI-RADS/USE
76.4 88.9⁎ 93.0⁎
85.0 91.8 93.7⁎
82.3 90.9⁎ 93.5⁎
69.6 83.1 87.0
88.9 94.8 96.7
⁎ Pb.05 compared to TI-RADS.
thyroid microcarcinomas had regular shape, clear boundary, no apparent microcalcification, and no obvious malignancy, resulting in a low TI-RADS score. There are also 21 false-positive nodules among those scored 4 points in TI-RADS system. Analysis showed that most of these false-positive nodules had irregular shapes, unclear boundaries, uneven echo, and even microcalcification foci, which raised their TI-RADS scores. Irregular shape and unclear boundary of thyroid nodules often suggest that their biological behavior can be aggressive. However, in benign lesions, inflammation and infiltration of lymphatic cells to surrounding tissues can also cause the cells to have irregular shapes and unclear boundaries. As a result of dystrophia, formation of calcium crystal or follicular atrophy, nodules of nodular goiter sometimes become largely calcified, and small areas of calcium deposition or microcalcification can also form [9]. As a consequence, the similarity in gray-scale ultrasonography features between benign and malignant nodules impose some difficulties in their differential diagnoses. However, in our study, 15 of the false-positive nodules scored b 3 points in USE system, which matched their pathological results, suggesting that the USE evaluation system could nicely supplement the TI-RADS system in the differential diagnosis of thyroid microcarcinoma [10]. USE was first introduced by Ophir et al. [11] that the elastic modulus distribution in soft tissues was acquired by applying external direct or indirect compressive force or shearing force to the tissues. Different from traditional two-dimensional gray-scale or color Doppler ultrasonography, USE could distinguish between tissues with the same acoustic impedance but different elastic modulus [12]. For risk assessment, USE differentiates benign and malignant thyroid nodules based on the hardness of the nodules. Benign nodules are softer as they are mainly composed of follicles and colloids. Malignant nodules are harder as the internal cancerous cells show a papillary growth pattern with varied differentiation degree, and the intracellular substances are rich in fiber, blood vessels, and psammoma bodies. Bojunga et al. [4] carried out a meta-analysis over the elastograms of 639 thyroid nodules and found that the sensitivity and specificity for diagnosing malignant nodules were 92% and 90% respectively, which was in accordance with our result of 88.9% sensitivity and 91.8% specificity. Notably, attention should be paid on factors that might cause false-positive or false-negative results when using USE. In our study, the USE scoring system reported 13 false-positive nodules and 8 false-negative nodules. This was likely because in some benign nodules the presence of calcification, fibrosis, or hyaline degeneration reduced the hardness of the tissue, leading to high USE scores. On the other hand, the internal bleeding and necrotic cystic degeneration in some malignant nodules might reduce the hardness of the nodules, leading to low scores and false-negative results. In addition, thyroid locates close to the surface of the body. The rigidity of the nodules is poorly reflected upon compression as they are easily affected by respiration and the pulsation of large neck vessels [12]. As a result, there will be a certain deviation when evaluating the malignancy risk of thyroid nodules solely based on USE results. However, the
916
J. Xue et al. / Clinical Imaging 40 (2016) 913–916
Fig. 2. The ROC of (A) TI-RADS (AUC=0.812), (B) USE (AUC=0.83) and (C) combined method (AUC=0.914).
diagnostic accuracy of USE is relatively higher than TI-RADS. In this study, the sensitivity, specificity, PPV, and NPV for USE were all significantly higher than TI-RADS (P b.05). However, there was no significant difference in the AUC of ROC between USE and TI-RADS, which matched the study by Unlütürk et al. that comparing to traditional gray-scale ultrasonography, there was no obvious advantage for using USE in the differential diagnoses of benign and malignant thyroid nodules [13]. The combined application of TI-RADS and USE provided the internal hardness profile of the nodules in addition to their ultrasonic morphology, forming new diagnostic standards. In this study, the number of false-negative and false-positive nodules was significantly less than TI-RADS. Among the five false-negative nodules two of them were follicular carcinomas, which were mainly comprised of follicles of different differentiation degrees. Follicles are normally small, well differentiated, without papilla or psammoma bodies within the tumor tissue. There were abundant parenchymal vessels within the mesenchyme which resembled the normal thyroid tissues due to their soft texture [14]. Therefore their USE scores were lower. The diagnostic sensitivity, specificity and accuracy of TI-RADS/USE combined system were 16.6%, 8.7%, and 11.2% respectively, suggesting that the combination of TI-RADS and USE could increase the detection rate of malignant nodules. This result was in accordance with the meta-analysis result by Trimboli et al. [15]. In summary, our study suggested that both gray-scale ultrasonography and USE had certain limitations in the differential diagnosis of benign and malignant thyroid nodules when applied on their own. The combination of these two methods could significantly increase the accuracy of diagnosis. Evaluation bias and deviations were unavoidable due to the sonographers' subjective factors. The study could also be improve by increasing the sample size in order to reduce the errors in verifying the efficacy of the TI-RADS scoring system. Future efforts will be made in identifying the optimal evaluation system for thyroid sonograms.
References [1] Iannuccilli JD, Cronan JJ, Monchik JM. Risk for malignancy of thyroid nodules as assessed by sonographic criteria: the need for biopsy. J Ultrasound Med 2004;23:1455–64. [2] Tee YY, Lowe AJ, Brand CA, Judson RT. Fine-needle aspiration may miss a third of all malignancy in palpable thyroid nodules: a comprehensive literature review. Ann Surg 2007;246:714–20. [3] Park JY, Lee HJ, Jang HW, Kim HK, Yi JH, Lee W, et al. A proposal for a thyroid imaging reporting and data system for ultrasound features of thyroid carcinoma. Thyroid 2009;19:1257–64. [4] Bojunga J, Herrmann E, Meyer G, Weber S, Zeuzem S, Friedrich-Rust M. Real-time elastography for the differentiation of benign and malignant thyroid nodules: a meta-analysis. Thyroid 2010;20:1145–50. [5] Horvath E, Majlis S, Rossi R, Franco C, Niedmann JP, Castro A, et al. An ultrasonogram reporting system for thyroid nodules stratifying cancer risk for clinical management. J Clin Endocrinol Metab 2009;94:1748–51. [6] Asteria C, Giovanardi A, Pizzocaro A, Cozzaglio L, Morabito A, Somalvico F, et al. USelastography in the differential diagnosis of benign and malignant thyroid nodules. Thyroid 2008;18:523–31. [7] Rubaltelli L, Corradin S, Dorigo A, Stabilito M, Tregnaghi A, Borsato S, et al. Differential diagnosis of benign and malignant thyroid nodules at elastosonography. Ultraschall Med 2009;30:175–9. [8] Wang B, Zhang H, Liu P. Ultrasound and pathology atlas of malignant thyroid tumors. 1st ed. Beijing: People's Medical Publishing House; 2014. [9] Lin XY, Lin LW, Xue ES, He YM, Lin XD, Yu LY. The diagnostic value of high-frequency ultrasound in nodular goiter combining thyroid microcacinoma. Chin J Med Imaging 2012;20:618–21 [In Chinese]. [10] Shao J, Li Q, Cao H, Zhang L, Li H, Xu S, et al. The value of thyroid imaging reporting and data system classification in combination with ultrasound elastography in the diagnosis of benign and malignant thyroid nodules. Chin J Med Ultrason 2013;10:31–5 [In Chinese]. [11] Ophir J, Céspedes I, Ponnekanti H, Yazdi Y, Li X. Elastography: a quantitative method for imaging the elasticity of biologicaltissues. Ultrason Imaging 1991;13:111–34. [12] Wang T, Wang XM, Zhang YX, Feng YQ, Tao CM. Quantitative analysis of the differential diagnosis of benign and malignant thyroid nodules by real-time shear wave elasticity imaging. Chin J Med Imaging 2012;20:684–7 [In Chinese]. [13] 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;22:1031–8. [14] Guo HF, Xue ES, Lin LW, He YM, Chen ZK. Sonographic characteristics and differentiation of follicular thyroid carcinoma and follicular adenoma. Chin J Med Ultrason 2013;10:106–9 [In Chinese]. [15] Trimboli P, Guglielmi R, Monti S, Misischi I, Graziano F, Nasrollah N, et al. Ultrasound sensitivity for thyroid malignancy is increased by real-time elastography: a prospective multicenter study. J Clin Endocrinol Metab 2012;97:4524–30.
Contents lists available at ScienceDirect
Clinical Imaging journal homepage: http://www.clinicalimaging.org
The diagnostic value of combination of TI-RADS and ultrasound elastography in the differentiation of benign and malignant thyroid nodules Jie Xue a,1, Xiao-li Cao a,1, Lei Shi a, Chun-hua Lin b, Jiahui Wang c, Lihong Wang a,⁎ a b c
Ultrasonic Department, Yantai Yuhuangding Hospital, Yantai, Shandong, 264000, China Urology Department, Yantai Yuhuangding Hospital, Yantai, Shandong, 264000, China Central Laboratory, Yantai Yuhuangding Hospital, Yantai, Shandong, 264000, China
a r t i c l e
i n f o
Article history: Received 17 March 2016 Received in revised form 19 April 2016 Accepted 27 April 2016 Available online xxxx Keywords: Thyroid imaging reporting and data system, TI-RADS Elasticity imaging techniques Thyroid nodule Ultrasonography
a b s t r a c t Background: Here, we evaluated the diagnostic value of combination of thyroid imaging-reporting and data system (TI-RADS) and ultrasound elastography (USE) in risk assessment of thyroid nodules. Methods: The clinical data of 174 patients with 232 nodules were retrospectively analyzed. All nodules were examined by gray-scale ultrasonography and USE and confirmed by histological examination. Results: The sensitivity, specificity, and accuracy of the combination of the two methods were significantly higher than those using a single method. Conclusion: The combination of TI-RADS and USE has high diagnostic sensitivity and accuracy in evaluating the malignant risk of thyroid nodules.
© 2016 Elsevier Inc. All rights reserved.
1. Background Ultrasonography is currently the major approach in the diagnosis of thyroid nodules. However the accuracy of ultrasonography is relatively low in differentiating benign and malignant thyroid nodules [1]. Fine needle aspiration (FNA) could be used as a supplement in evaluating the risk of thyroid nodules ≧10 mm. However, despite its high specificity of 60%–98%, the diagnostic sensitivity of FNA could be as low as 65–68% [2]. Many patients underwent operation without a definite qualitative diagnosis, which placed extra physical, psychological, and economic burdens to the patients. To avoid unnecessary biopsy and operation, the thyroid imaging-reporting and data system (TI-RADS) was developed by Parker et al. for risk stratification of thyroid nodules [3]. However, TI-RADS has been limited in clinical application and questioned for its feasibility and practicability due to the practice being too subjective. In recent years, ultrasound elastography (USE) has been increasingly used in the risk assessment of thyroid nodules. A meta-analysis reported 92% overall mean sensitivity and 90% specificity for the diagnosis of malignant thyroid nodules by USE, respectively [4]. In this study, we investigated and discussed the clinical value of
⁎ Corresponding author. Yantai Yuhuangding Hospital, 20 Yuhuangding East Road, Yantai, Shandong, 264000, China. Tel.: +86-535-6691999. E-mail address: [email protected] (L. Wang). 1 Equal contribution. http://dx.doi.org/10.1016/j.clinimag.2016.04.014 0899-7071/© 2016 Elsevier Inc. All rights reserved.
the combination of TI-RADS and USE in the differential diagnosis of benign and malignant thyroid nodules. 2. Material and methods 2.1. Patients In this retrospective study, 232 nodules in 174 consecutive patients (72 male, 102 female, aged 25–58 years old, median age 43.4) admitted to Yantai Yuhuangding Hospital between September 2011 and December 2013 were examined. The inclusion criteria were patients with solid or cystic-solid mixed nodules that were ≧5 mm, without “egg-shell” calcification on the edge, and surrounding thyroid tissues were normal. For multiple nodules, the large ones or those with malignant probability were chosen. All nodules were examined by gray-scale ultrasonography and USE examinations, and final diagnoses were obtained from pathological evaluation. The maximum diameters of nodules ranged from 7 to 24 mm. This study was approved by the Ethics Committee of Yantai Yuhuangding Hospital. Written informed consents were obtained from patients before all examinations and treatments for the inclusion of clinical data for scientific research and publication purpose. 2.2. Imaging techniques US examinations for all patients were performed by the same physician.
914
J. Xue et al. / Clinical Imaging 40 (2016) 913–916
Ultrasonography was performed using two ultrasound systems (LogicE9, GE Healthcare, Milwaukee, WI, USA; Aplio™ 500, Toshiba Medical Systems Co. Ltd., Otawara, Japan). Patients took the spine position with adequate exposure of the neck. The thyroid was scanned from the anterior aspect of the neck at different angles (transverse, sagittal, and oblique). Information of the nodules including their location, number, size, shape, boundary, aspect ratio (the ratio of the longitudinal against the axial length), internal echo, ultrasound attenuation and microcalcification as well as any enlargement of cervical lymph nodes were recorded. Extra attention was paid to the lymph nodes at area 3, 4, 6, and 5 (5 A and 5B) of bilateral neck. The characteristics of thyroid nodules were valuated with two-dimensional gray-scale ultrasonography. For USE examination, the sampling frame of the region of interest (ROI) included the nodules and the surrounding normal thyroid tissue. The probe made slight vibrations upon the nodules at a frequency of twice per second and a depth of pressure of 1–2 mm until it reached the optimal pressure and frequency, which showed all green in the indicator shaft for Logic E9 or regular waveform curves for Aplio 500 scanner. The gray-scale images and elastograms were real-time displayed and monitored simultaneously. The elasticity of diverse tissues was represented by different colors in the elasotogram. Green represented the average tissue hardness within the ROI. Red indicated softer tissues than the average, and blue suggested harder tissues. The color distribution of each nodule was recorded and classified. 2.3. Scoring system Retrospective investigation was done by Medical Picture Archiving and Communication System (Medicon Digital Engineering Co. LTD, Qingdao, China). All ultrasonic images were independently evaluated by two physicians with at least five years of ultrasound work experience. In case of disagreement, the image was evaluated by a third associate chief physician with more than seven years of ultrasound work experience until consensus was reached upon discussion. The thyroid nodules were scored according to the TI-RADS scoring system [5]: TI-RADS 1 (Score 1): normal thyroid or diffuse hyperplasia of thyroid. TI-RADS 2 (Score 2): benign conditions, mainly included the glial Type I, II and III nodules. TI-RADS 3 (Score 3): probably benign nodules, mostly seen in the Hashimoto's thyroiditis. TI-RADS 4 A (Score 4): indeterminate nodules (malignancy between 5 and 10%), including solid iso-echoic nodules or mix-echoic nodules coated in capsules; hypoechoic nodules with unclear boundaries and no calcification; calcified nodules coated in thick capsules and with rich blood supply. TI-RADS 4B (Score 5): suspicious nodules (malignancy between 10 and 80%), which are hypochoic, no capsule, with irregular form and boundaries, with perforator blood vessels and with/without calcification. TI-RADS 5 (Score 6): probably malignant nodules, which are isoechoic or hypochoic, no capsule, with rich blood supply and microcalcification. Score 1–3 were classified as benign and 4–6 as malignant. We also scored the nodules using the USE scoring system by Asteria et al. [6] and Rubaltelli et al. [7]: Score 1: elasticity in the whole examined area (all green). Score 2: elasticity in a large part of the examined area (majority of the nodule area was green with a little blue area). Score 3: stiffness in a large part of the examined area (majority of the nodule area was blue with a little green area). Score 4: a nodule without elasticity (all blue). Score 1–2 were classified as benign and 3–4 as malignant.
For combined TI-RADS/USE diagnosis, the TI-RADS score and USE score of each nodule were added. A final score of 2–6 were considered benign nodules and 7–10 were malignant nodules. Pathological results were used as a golden standard for evaluating the diagnosis value of TI-RADS/USE combined system in risk assessment of thyroid nodules. 2.4. Pathological diagnosis Tissue samples of each nodule were obtained from operation or ultrasound-guided core biopsy. Surgically resected nodules were subjected to intra-operative frozen section for preliminary risk assessment. Final diagnosis was based on postoperative paraffin section pathological examinations. Nodule tissues obtained from biopsy were fixed in paraformaldehyde and subjected to paraffin section pathological examinations. In case of suspicious malignant samples or atypical samples, immunohistochemical staining was applied to differentiate benign and malignant nodules. If biopsy suggested follicular carcinoma, the whole tumor was surgically removed for definite diagnosis. Benign nodules mainly comprised nodular goiter, glial nodules, adenoma, and Hashimoto's thyroiditis. Malignant nodules were mainly papillary carcinoma, in less case follicular and medullary carcinoma, and occasionally thyroid lymphoma. 2.5. Statistics Statistical analysis was performed using the Statistical Product and Service Solutions 17.0 software. The diagnostic efficacy of USE and TIRADS were compared by sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) using χ2-test. Receiver operating characteristic curve (ROC) was plotted, and area under the curve (AUC) was calculated. Z-test was utilized to compare the AUC of ROC. Pb .05 indicated statistically significant difference. 3. Results The diagnosis of the 232 nodules by TI-RADS scoring, USE scoring, combined TI-RADS/USE scoring, and pathological diagnoses was summarized in Table 1. Pathological tests showed that 160 were benign and 72 were malignant (69 papillary carcinomas, 3 follicular carcinomas). Based on the TI-RADS score, 153 nodules were benign (92 nodules scored 2, 61 scored 3), and 79 were malignant (52 scored 4 or 5 points, 27 scored 6). Based on the USE scores, there were 153 benign nodules (53 nodules scored 1, 102 scored 2) and 77 malignant nodules (32 nodules scored 3, 45 scored 4). Based on combined TI-RADS/USE scores, there were 155 benign nodules and 77 malignant nodules (Fig. 1). Our result showed that both the sensitivity and accuracy of USE evaluation system were significantly higher than the TI-RADS system alone (χ 2 =3.920, 7.446. P b .05). In case of combined TI-RADS/USE scoring, there was a significant improvement in the sensitivity, specificity, and accuracy of diagnosis than TI-RADS (χ2 =7.725, 6.450, 13.728. P b.05) (Table 2). The ROC of TI-RADS, USE, and combined TI-RADS/USE analysis were individually plotted (Fig. 2), and their AUC were calculated. Result showed that the AUC for TI-RADS diagnosis system was 0.812 with standard error 0.032, 95% confidence interval (CI)=0.749–0.874. The AUC for USE diagnosis system was 0.833; standard error, 0.034; 95% CI=0.767–0.899. The AUC for combined TI-RADS/USE diagnosis system Table 1 The number of nodules in each diagnostic group based on the TI-RADS, USE, and combined TI-RADS/USE scoring system Pathological classification
TI-RADS
Benign Malignant
136 17
USE
TI-RADS/USE
Benign Malignant Benign Malignant Benign Malignant 24 55
147 8
13 64
150 5
10 67
J. Xue et al. / Clinical Imaging 40 (2016) 913–916
915
Fig. 1. A 56-year-old female patient with papillary thyroid carcinoma. (A) Gray-scale ultrasonography showed a hypoechoic nodule in the right thyroid lobe with maximum diameter N10 mm, unclear boundary, uneven internal echo, and no calcification foci. It scored 3 points in TI-RADS system, suggesting possible benign nodule. (B) USE showed stiffness in a large part of the nodule area and scored 3 points, suggesting malignant nodule. (C) Hematoxylin-Eosin staining of the pathological section, visualized under microscope at ×100. Result showed follicular epithelial papillary hyperplasia infiltrating to surrounding tissues. Nuclei of glass appearance, nuclear grooves, and intranuclear pseudoinclusions were observed. Cell nuclei were enlarged and lightly colored.
was 0.914; standard error, 0.024; 95% CI=0.868–0.960. There was no significant difference between the AUC of TI-RADS and USE (Z=0.45, PN.05). The AUC for combined TI-RADS/USE was significantly different from that of USE or TI-RADS (Z=1.95 and 2.55, Pb.05). 4. Discussion A thyroid nodule is the most common thyroid diseases and epidemiologic studies have revealed an increasing morbidity each year [8]. It has become a research hotspot to increase the diagnostic accuracy for differentiation between benign and malignant thyroid nodules. Ultrasonography is able to not only differentiate solid nodules to cystic nodules but also facilitate the differential diagnosis of benign and malignant nodules based on the ultrasonic characteristics including the location, form, size, echo, calcification, echo halo, boundary, and internal blood flow of the nodules. There is no single ultrasound feature that can provide enough accuracy in the differential diagnosis of benign and malignant thyroid nodules. The combination of multiple ultrasound features will greatly improve the diagnostic sensitivity and specificity. Therefore Park et al. proposed the TI-RADS system to predict the probability of malignancy in thyroid nodules based on the features of thyroid nodules as noted on ultrasound [3]. In this study, the TI-RADS scoring system achieved a sensitivity of 76.4%, specificity 85.0%, accuracy 82.3%, PPV 69.6%, and NPV 88.9%. Our specificity was lower than reported by Horvath et al., which is 88% [5], suggesting misdiagnosis of malignant nodules. This was probably due to that thyroid tumors, inflammation or hyperplasia caused overlaps in ultrasound features, interfering the subjective judgment of observer. In this study, 12 pathologically confirmed malignant nodules were false diagnosed as benign by the TI-RADS system (scored 3 points). Among them 9 nodules were diagnosed correctly by the USE system (scored N2). Our study showed that 5 of the false-negative nodules were thyroid microcarcinoma with a maximum diameter of b10 mm. The gray-scale ultrasonography for thyroid microcarcinoma features low echo-level, no acoustic halo, microcalcification, no cystic degeneration, and others [9], none of which is the specific symptom of diagnosing thyroid microcarcinoma. Therefore, it is likely to be confused with or masked by the acoustic phase of nodular goiter. In this study, the
Table 2 Comparison of the diagnostic efficacy among the TI-RADS, USE, and combined TI-RADS/ USE evaluation system (%) Evaluation method
Sensitivity
Specificity
Accuracy
PPV
NPV
TI-RADS USE TI-RADS/USE
76.4 88.9⁎ 93.0⁎
85.0 91.8 93.7⁎
82.3 90.9⁎ 93.5⁎
69.6 83.1 87.0
88.9 94.8 96.7
⁎ Pb.05 compared to TI-RADS.
thyroid microcarcinomas had regular shape, clear boundary, no apparent microcalcification, and no obvious malignancy, resulting in a low TI-RADS score. There are also 21 false-positive nodules among those scored 4 points in TI-RADS system. Analysis showed that most of these false-positive nodules had irregular shapes, unclear boundaries, uneven echo, and even microcalcification foci, which raised their TI-RADS scores. Irregular shape and unclear boundary of thyroid nodules often suggest that their biological behavior can be aggressive. However, in benign lesions, inflammation and infiltration of lymphatic cells to surrounding tissues can also cause the cells to have irregular shapes and unclear boundaries. As a result of dystrophia, formation of calcium crystal or follicular atrophy, nodules of nodular goiter sometimes become largely calcified, and small areas of calcium deposition or microcalcification can also form [9]. As a consequence, the similarity in gray-scale ultrasonography features between benign and malignant nodules impose some difficulties in their differential diagnoses. However, in our study, 15 of the false-positive nodules scored b 3 points in USE system, which matched their pathological results, suggesting that the USE evaluation system could nicely supplement the TI-RADS system in the differential diagnosis of thyroid microcarcinoma [10]. USE was first introduced by Ophir et al. [11] that the elastic modulus distribution in soft tissues was acquired by applying external direct or indirect compressive force or shearing force to the tissues. Different from traditional two-dimensional gray-scale or color Doppler ultrasonography, USE could distinguish between tissues with the same acoustic impedance but different elastic modulus [12]. For risk assessment, USE differentiates benign and malignant thyroid nodules based on the hardness of the nodules. Benign nodules are softer as they are mainly composed of follicles and colloids. Malignant nodules are harder as the internal cancerous cells show a papillary growth pattern with varied differentiation degree, and the intracellular substances are rich in fiber, blood vessels, and psammoma bodies. Bojunga et al. [4] carried out a meta-analysis over the elastograms of 639 thyroid nodules and found that the sensitivity and specificity for diagnosing malignant nodules were 92% and 90% respectively, which was in accordance with our result of 88.9% sensitivity and 91.8% specificity. Notably, attention should be paid on factors that might cause false-positive or false-negative results when using USE. In our study, the USE scoring system reported 13 false-positive nodules and 8 false-negative nodules. This was likely because in some benign nodules the presence of calcification, fibrosis, or hyaline degeneration reduced the hardness of the tissue, leading to high USE scores. On the other hand, the internal bleeding and necrotic cystic degeneration in some malignant nodules might reduce the hardness of the nodules, leading to low scores and false-negative results. In addition, thyroid locates close to the surface of the body. The rigidity of the nodules is poorly reflected upon compression as they are easily affected by respiration and the pulsation of large neck vessels [12]. As a result, there will be a certain deviation when evaluating the malignancy risk of thyroid nodules solely based on USE results. However, the
916
J. Xue et al. / Clinical Imaging 40 (2016) 913–916
Fig. 2. The ROC of (A) TI-RADS (AUC=0.812), (B) USE (AUC=0.83) and (C) combined method (AUC=0.914).
diagnostic accuracy of USE is relatively higher than TI-RADS. In this study, the sensitivity, specificity, PPV, and NPV for USE were all significantly higher than TI-RADS (P b.05). However, there was no significant difference in the AUC of ROC between USE and TI-RADS, which matched the study by Unlütürk et al. that comparing to traditional gray-scale ultrasonography, there was no obvious advantage for using USE in the differential diagnoses of benign and malignant thyroid nodules [13]. The combined application of TI-RADS and USE provided the internal hardness profile of the nodules in addition to their ultrasonic morphology, forming new diagnostic standards. In this study, the number of false-negative and false-positive nodules was significantly less than TI-RADS. Among the five false-negative nodules two of them were follicular carcinomas, which were mainly comprised of follicles of different differentiation degrees. Follicles are normally small, well differentiated, without papilla or psammoma bodies within the tumor tissue. There were abundant parenchymal vessels within the mesenchyme which resembled the normal thyroid tissues due to their soft texture [14]. Therefore their USE scores were lower. The diagnostic sensitivity, specificity and accuracy of TI-RADS/USE combined system were 16.6%, 8.7%, and 11.2% respectively, suggesting that the combination of TI-RADS and USE could increase the detection rate of malignant nodules. This result was in accordance with the meta-analysis result by Trimboli et al. [15]. In summary, our study suggested that both gray-scale ultrasonography and USE had certain limitations in the differential diagnosis of benign and malignant thyroid nodules when applied on their own. The combination of these two methods could significantly increase the accuracy of diagnosis. Evaluation bias and deviations were unavoidable due to the sonographers' subjective factors. The study could also be improve by increasing the sample size in order to reduce the errors in verifying the efficacy of the TI-RADS scoring system. Future efforts will be made in identifying the optimal evaluation system for thyroid sonograms.
References [1] Iannuccilli JD, Cronan JJ, Monchik JM. Risk for malignancy of thyroid nodules as assessed by sonographic criteria: the need for biopsy. J Ultrasound Med 2004;23:1455–64. [2] Tee YY, Lowe AJ, Brand CA, Judson RT. Fine-needle aspiration may miss a third of all malignancy in palpable thyroid nodules: a comprehensive literature review. Ann Surg 2007;246:714–20. [3] Park JY, Lee HJ, Jang HW, Kim HK, Yi JH, Lee W, et al. A proposal for a thyroid imaging reporting and data system for ultrasound features of thyroid carcinoma. Thyroid 2009;19:1257–64. [4] Bojunga J, Herrmann E, Meyer G, Weber S, Zeuzem S, Friedrich-Rust M. Real-time elastography for the differentiation of benign and malignant thyroid nodules: a meta-analysis. Thyroid 2010;20:1145–50. [5] Horvath E, Majlis S, Rossi R, Franco C, Niedmann JP, Castro A, et al. An ultrasonogram reporting system for thyroid nodules stratifying cancer risk for clinical management. J Clin Endocrinol Metab 2009;94:1748–51. [6] Asteria C, Giovanardi A, Pizzocaro A, Cozzaglio L, Morabito A, Somalvico F, et al. USelastography in the differential diagnosis of benign and malignant thyroid nodules. Thyroid 2008;18:523–31. [7] Rubaltelli L, Corradin S, Dorigo A, Stabilito M, Tregnaghi A, Borsato S, et al. Differential diagnosis of benign and malignant thyroid nodules at elastosonography. Ultraschall Med 2009;30:175–9. [8] Wang B, Zhang H, Liu P. Ultrasound and pathology atlas of malignant thyroid tumors. 1st ed. Beijing: People's Medical Publishing House; 2014. [9] Lin XY, Lin LW, Xue ES, He YM, Lin XD, Yu LY. The diagnostic value of high-frequency ultrasound in nodular goiter combining thyroid microcacinoma. Chin J Med Imaging 2012;20:618–21 [In Chinese]. [10] Shao J, Li Q, Cao H, Zhang L, Li H, Xu S, et al. The value of thyroid imaging reporting and data system classification in combination with ultrasound elastography in the diagnosis of benign and malignant thyroid nodules. Chin J Med Ultrason 2013;10:31–5 [In Chinese]. [11] Ophir J, Céspedes I, Ponnekanti H, Yazdi Y, Li X. Elastography: a quantitative method for imaging the elasticity of biologicaltissues. Ultrason Imaging 1991;13:111–34. [12] Wang T, Wang XM, Zhang YX, Feng YQ, Tao CM. Quantitative analysis of the differential diagnosis of benign and malignant thyroid nodules by real-time shear wave elasticity imaging. Chin J Med Imaging 2012;20:684–7 [In Chinese]. [13] 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;22:1031–8. [14] Guo HF, Xue ES, Lin LW, He YM, Chen ZK. Sonographic characteristics and differentiation of follicular thyroid carcinoma and follicular adenoma. Chin J Med Ultrason 2013;10:106–9 [In Chinese]. [15] Trimboli P, Guglielmi R, Monti S, Misischi I, Graziano F, Nasrollah N, et al. Ultrasound sensitivity for thyroid malignancy is increased by real-time elastography: a prospective multicenter study. J Clin Endocrinol Metab 2012;97:4524–30.