.N.though. Thyroid Nodules: Evaluation with Color Doppler Ultrasonography MATERIALS AND METHODS

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1 Thyroid Nodules: Evaluation with Color Doppler Ultrasonography Kazuhiro Shimamoto, MD, Tokiko Endo, MD, Takeo Ishigaki, MD, Sadayuki Sakuma, MD, Naoki Makino, MD Forty-seven patients with thyroid nodules (13 papillary carcinomas, 14 adenomas, and 20 adenomatous goiters) underwent color Doppler sonography with a 7.5 MHz transducer. Perinodular or intranodular color flow signals were depicted in 10 of 13 papillary carcinomas, in 10 of 14 follicular adenomas, and in 14 of 20 adenomatous goiters. No correlation existed between the presence of color signals and pathology, whereas the detection rate of color signals had a dependence on the size of the lesions. No specific flow pattern for malignancy could be found. Color Doppler sonography would not improve the ability to differentiate benign from malignant nodules significantly. KEY WORDS: Thyroid neoplasms; Thyroid nodule; Color Doppler US. sonography is widely used as a simple and noninvasive diagnostic tool in a.n.though wide spectrum of thyroid diseases, the lack of histopathological specificity accentuates its limitation.l-l On the other hand, color Doppler sonography provides not only the standard gray scale image but also a color display of blood flow and hence permits the evaluation of vascularity in thyroid tumors and tumorlike lesions. This could be a useful tool in the differential diagnosis of thyroid disease. 4-6 However, it is not yet clear that an analysis of flow pattern types could differentiate carcinomas from benign lesions. This study therefore attempted to assess the characteristics of blood flow within the thyroid nodules with the emphasis on the correlation between flow patterns and pathology. The relationship between color Doppler patterns and the gray scale appearance of the lesions also was evaluated. Received January 22, 1993, from the Department of Radiology, Nagoya University School of Medicine, Nagoya, Japan. Revised manuscript accepted for publication May 4, Address correspondence and reprint requests to Kazuhiro Shi mamoto, MD, Department of Radiology, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466 Japan. MATERIALS AND METHODS From July 1990 to March 1992, 229 patients with thyroid nodules underwent examination with color Doppler sonography at the Department of Radiology in Nagoya University Hospital. Forty-seven patients (41 female, six male) with pathologic proof obtained by surgical resection were selected for the study. The age varied from 20 to 78 years (average, 46 years). There were 13 papillary carcinomas, 14 follicular adenomas, and 20 adenomatous goiters. The nodules were 0.7 to 8.0 em in diameter (average, 3.0 em). In cases with multiple nodules, the largest one was selected for color Doppler study. There were no patients with so many nodules that uncertainty existed as to which one was biopsied. Color Doppler sonography was performed using a commercially available color Doppler system (EUB- 515; Hitachi, Tokyo, Japan) with a 7.5 MHz transducer. The patients first underwent the gray scale scanning, and subsequently color flow imaging and the Doppler examination were performed with the help of breath holding. With conventional 8-mode scanning, typically, a hypoechoic, solid nodule with heterogeneous inter- () 1993 by the American Institute of Ultrasound in Medicine J Ultrasound Med 12: , /93/$3.50

2 674 THYROID NODULES J Ultrasound Med 12: , 1993 Figure 1 Papillary carcinoma. Sagittal scan of the left lobe shows a poorly defined hypoechoic mass with calcification. A spotty color area is depicted at the periphery of the lesion. Figure 2 Follicular adenoma. Sagittal scan shows marked color flow surrounding the nodule (the color "halo" sign). Increased blood flow also is depicted at the center of the tumor. nal echoes and an irregular border was regarded as malignant, whereas a well defined nodule with ho mogeneous internal echoes or with cystic space and without disruption of the "halo" was regarded as benign.t-3 With color flow imaging, flow toward the transducer was displayed as red, whereas blue indicated flow in the reverse direction. A reference of 5 MHz, a wall filter of 50 or 100 Hz, and a pulse repetition frequency of 120 Hz to 1 khz (usually 400 or 500 Hz) were used. Theoretically, the minimal blood flow velocity that could be depicted was 1.1 em/sec at a 45 degree angle of incidence. Color gain was adjusted to a level associated with minimal artifacts. Nodules were classified into four groups on the basis of flow distribution as follows: 1. Type 0: Absence of color signals. 2. Type 1: lntranodular color signals of spotty or patchy appearance but lacking perinodular color signals (Fig. 1). 3. Type II: Prominent color flow at the periphery of the nodule, showing basketli.ke appearance with or without color signals at the center (color "halo" sign) (Fig. 2). 4. Type III: Marked color flow throughout the entire nodule, including the "inferno" pattern described by Ralls and coworkers4 (Fig. 3). The color flow image was used as a guide to select the points for recording the Doppler time-velocity waveform with a sampling volume of 3 mm. When no color signals could be depicted, the quantitative Doppler examination was not performed. The Doppler waveform recorded at the point with the highest frequency shift was used for statistical analysis (nonparametric Wilcoxon rank-sum test was applied). For quantitative Doppler evaluation, the peak systolic frequency shift and the resistive index (peak systolic frequency shift - end-diastolic frequency shift/peak systolic frequency shift) were used. The angle correc tion was not employed because in most cases the vasculature visualized within the nodule was too small or tortuous to allow it. Figure 3 Papillary carcinoma. Sagittal scan shows a poorly defined mass with marked color flow signals throughout the entire nodule. Calcification and cystic degeneration are lacking.

3 J Ultrasound Med 12: , 1993 SHIMAMOTO ET At 675 Table 1: Correlation Between Pathology and Color Doppler Findings Pathology No. of Flow Pattern 11f (khz) Resistive Index Cases 0 II III Range Mean± Range Mean± SD so Papillary carcinoma ± ± 0.20 Follicular adenoma ± ± 0.25 Adenomatous goiter ± ± 0.22 Nodules without color signals were excluded for analysis of Doppler data; 11f, peak systolic frequency shift. for flow pattern: 0, absence of color flow; I, presence of intranodular color signals of spotty or patchy appearance; II, prominent perinodular color "halo" with or without intranodular color flow; III, marked color flow throughout the entire nodule. RESULTS In our series of 47 patients, 12 of 13 papillary carcinomas were correctly diagnosed with conventional B-mode scanning. There was one false-negative case that appeared as an isoechoic nodule with a cystic component. Six false-positive cases showed inhomogeneous echogenicity with or without calcification. Therefore, the sensitivity, the specificity, and the accuracy rate in differentiating benign from malignant lesions were 92.3, 82.4, and 85.1%, respectively. Correlation between pathologic and color Doppler findings is summarized in Table 1. Color signals could be depicted in 10 of 13 (76.9%) papillary carcinoma cases, in 10 of 14 (71.4%) fouicular adenoma cases, and in 14 of 20 (70.0%) adenomataus goiter cases. No correlation existed between the presence of color flow signals and pathology. Similarly, no significant correlation was found between the average of Doppler data and pathology. No lesion had a peak systolic frequency shift exceeding 5.0 khz. As regards the blood flow distribution, type II or III was seen in 14 of 34 (41.2%) benign lesions and in two of 13 (15.4%) papillary carcinomas. Malignant nodules showed a greater tendency to exhibit type I flow than benign lesions (P < 0.05). However, no specific flow pattern for malignancy could be found. Similarly, no color flow pattern that correlated specifically with the conventional B-mode characteristics of the nodules (echogenicity and the presence of cystic degeneration) could be found (Table 2). Furthermore, no correlation existed between the flow patterns and the Doppler data (Table 3). Follicular components were found microscopically in two patients with papillary cancer. However, the number of cases was too small to decide whether the presence of follicular components affected the flow pattern or Doppler data. The Doppler waveform differed at several points within a nodule. In every nodule with color signals, pulsatile blood flow could be recorded. Continuous flow could be recorded in four of 13 (30.8%) papillary carcinomas, in three of 14 (21.4%) follicular adenomas, and in six of 20 (30.0%) adenomatous goiters. The presence or absence of continuous flow did not contribute to the differential diagnosis of thyroid nodules. The color flow signals could be depicted in one of four (25.0%) papillary carcinomas and in eight of 15 (53.3%) benign lesions less than 2.0 em in diameter, whereas they were depicted in nine of nine (100%) malignant tumors and in 16 of 19 (84.2%) benign lesions greater than 2.0 em in diameter. The detection rate of color signals in nodules greater than 2.0 em in diameter was significantly higher than in those with less than 2.0 em diameter in both malignant tumors (P < 0.01) and benign lesions (P < 0.05). But, as shown in Table 3, no significant difference was found between the Doppler data of nodules less than 2.0 em Table 2: Correlation Between B-Mode Images and Flow Patterns Echogenidty Cystic No. of Flow Pattern t of Nodule Degeneration Cases 0 II III Hypoechoic (+) (-) Isoechoic or (+) hyperechoic (-) for cystic degeneration: ( + ), present; (-), absent. tfor flow pattern: 0, absence of color flow; I, presence of intranodular color signals of spotty or patchy appearance; II, prominent perinodular color "halo" with or without intranodular color flow; Ill, marked color flow throughout the entire nodule.

4 676 THYROID NODULES J Ultrasound Med 12: , 1993 Table 3: Quantitative Evaluation of Blood Flow Depending on Flow Pattern and Conventional B-Mode Images Criterion Flow pattemt No. of Cases of Color Flow TypeD 13 (+) (- ) 11f (khz) Quantitative Doppler Data Resistive Index Type I ± ± 0.22 Type II ± ± 0.22 Type III ± ± 0.27 Nodule size s2.0 em ± ± 0.16 >2.0 em :!:: ± 0.25 Calcification (+) ::!; ± 0.17 (- ) ± ± 0.25 Cystic degeneration (+) ~ ± 0.26 (- ) ± ± 0.20 Echogenicity of nodule Hypoechoic ± ± 0.26 Isoechoic or hyperechoic ± ± 0.20 Nodules without color signals were excluded for analysis of Doppler data; Af, peak systolic frequency shift. for color flow: (+), depicted;(- ), not depicted. For flow pattern: 0, absence of color flow; I, presence of intranodular color signals of spotty or patchy appearance; Jl, prominent perinodular color "halo" with or without intranodular color flow; Ill. marked color flow throughout the entire nodule. in diameter and those greater than 2.0 em in diameter. Also, no correlation was found between the range of detected Doppler frequency shifts and the presence of calcification and cystic degeneration. Similarly, no significant correlation existed between the Doppler data and the echogenicity of nodules. DISCUSSION The accuracy rate of the B-mode sonography in djfferentiating benign from malignant lesions has been reported to be 63 to 83%.7 8 Our 85% accuracy was somewhat high, but the number of cases in our series was small compared with their studies. As the technology to detect slow flow by co.lor Doppler sonography expands, the potential exists for increased applicability to vascular neoplasms. 9-tl In thyroid color Doppler sonography, color flow signals usually demonstrate pathologic vasculature because only a few vessels can be depicted in the normal thyroid gland. 4-6 In the early reports4.s emphasizing increased blood flow in Graves' disease, the usefulness of color Doppler sonography in differentiating benign from malignant lesions was also suggested. Fobbe and colleagues, 6 using a 7.5 MHz transducer with a Doppler filter of 150Hz, reported that 56 of 61 multinodular goiters showed normal vascularization and that the absence of increased vascularity would appear to be an important finding for excluding autonomous adenoma and thyroid carcinoma. However, our results suggested that the presence or absence of color signals did not enable us to establish the nature of thyroid nodules and that the detection rate of color signals depended on the size of the nodules rather than tumor pathology. There were several cases with adenomatous goiter or adenoma that were relatively "hypervascular" at color flow imaging compared with papillary cancer. This discrepancy perhaps would be due to the development of technological improvements in the detectable range of blood flow. Fukunaritl reported that the larger the adenomas, the more the blood flow volume of tht: superior thyroid artery increased with the help of duplex scanning. In our study, although blood flow of the superior thyroid artery was not evaluated, the correlation between nodule size and the detection rate of color signals could be observed. The size of the nodule may be a more important factor to demonstrate an increase in blood flow within the nodule than the pathological difference.t3 Schwaighofer and coworkers,s using a 7.5 MHz transducer wi.th a Doppler filter of 100 Hz, reported

5 J Ultrasound Med 12: , 1993 that autonomous adenomas had a hypervascular pe~ riphery and that carcinomas showed a hypervascu larization in the nodules. Consistent with their report, our results showed that the color "halo" sign was relatively infrequent in papillary cancer. Although the color "halo" sign is not specific for benign lesions, this finding will have a diagnostic value similar to the sonolucent "halo" sign on the standard gray scale sonography. Further study is necessary to decide whether the source of the color "halo" is from the displaced normal, surrounding vessels or the tumor vessels. On the other hand, papillary carcinomas exhibited type I flow more frequently than benign nodules. Papillary carcinomas seemed to be less vascular compared with benign lesions, because a nodule with type I flow was considered "hypovascular" compared to a nodule with type III flow. However, as shown angiographically,t4,t5 most malignant tumors are rich in irregular, tortuous vessels. This discrepancy might occur because color Doppler sonography is relatively less "sensitive" in the depiction of fine tumor vessels than angiography. With the advent of recent color Doppler systems, the minimal threshold for depicting blood flow is theoretically about 1 em/ sec. "Sensitivity" in color Doppler sonography relates to several factors (gain setting, pulse repetition frequency, Doppler filter, and frame rate), and tech~ nical difficulty also exists in selecting the precise setting at which optimal image is obtained.t 6 Depiction of fine vasculature with slow flow is still difficult. Therefore, "vascularity" on color flow imaging does not always correspond well to that on microscopic examination or angiograms. Color Doppler sonography may not assess the irregularity of fine vessels or the contour of the staining, which are evaluated easily with angiography. Considering the quantitative evaluation of flow, our results showed that no correlation existed between pathology and the peak systolic frequency shift or the resistive index obtained from the Doppler waveform. Similarly, no correlation was found between conventional B-mode images and the Doppler data. The Doppler examination would play a limited role in evaluating the nature of diseased vasculature within the nodules. Taylor and coworkers 17 reported that Doppler shifts greater than 3 khz at an insonating frequency shift of 3 MHz were detected in 38 of 47 patients with primary malignant tumors of the liver, kidney, adrenal gland, or pancreas and that such high~velocity Doppler signals were due to arteriovenous shunting. In our series, no lesion had a frequency shift exceeding 5.0 khz. (A 5.0 khz Doppler shift at a reference of 5.0 MHz correlates to a 3 khz shift used in their SHIMAMOTO ET AL 677 study.) But early visualization of the thyroid vein is not a typical finding for thyroid cancer.t4 The exact cause of this discrepancy remains to be identified but it probably was due to the lack of arteriovenous shunting. In conclusion, the presence of color flow signals, depending on the size of the nodule rather than on pathology, did not establish the diagnosis of thyroid cancer. The evaluation of flow distribution within the nodules will be moderately useful in some areas (such as the color "halo" sign). However, the nonspecificity of the color Doppler patterns could not significantly improve the limitation of the conventional B-mode scan. Furthermore, the quantitative Doppler evaluation of flow was of little value for the differential diagnosis of the thyroid tumor and tumorlike lesions. REFERENCES 1. Katz JF, Kane RA, Reyes J, et al: Thyroid nodules: Sonographic-pathologic correlation. Radiology 151:741, Ross OS: Evaluation of the thyroid nodules. J Nucl Med 32:2181, Cole-Beuglet C, Goldberg BB: New high-resolution ultrasound evaluation of disease of the thyroid. JAMA 249:2941, Ralls PW, Mayekawa DS, Lee KP, et al: Color-flow Doppler sonography in Graves' disease: "Thyroid in~ femo." AJR 150:781, Schwaighofer VB, Kurtaran A, Hubsch P, et al: Colorcoded Doppler sonography in thyroid gland diagnosis: Preliminary results. ROFO 149:310, Fobbe F, Finke R, Reichenstein E, et al: Appearance of duplex sonogra thyroid disease using colour~oded phy. Eur J Radial 9:29, Solbiati L, Volterrani L, Rizzatto G, et al: The thyroid gland with low uptake lesions: Evaluation by ultra sound. Radiology 155:187, Murakami T, Murakami N, Noguchi 5, et al: Ultrasonographic diagnosis of nodular goiter. Jpn J Med Ultrasonics 15:264, Scout LM, Zawin ML, Taylor KJW: Doppler US. Part II. Clinical applications. Radiology 174:309, Shimamoto K, Sakuma S, Ishigaki T, et al: Hepatocellular carcinoma: Evaluation with color Doppler US and MR imaging. 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