Can Color Doppler Sonography Aid in the Prediction of Malignancy of Thyroid Nodules?

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1 Article Can Color Doppler Sonography Aid in the Prediction of Malignancy of Thyroid Nodules? Mary C. Frates, MD, Carol B. Benson, MD, Peter M. Doubilet, MD, PhD, Edmund S. Cibas, MD, Ellen Marqusee, MD Objective. To determine whether color Doppler interrogation of a thyroid nodule can aid in the prediction of malignancy. Methods. We obtained color Doppler images of thyroid nodules undergoing sonographically guided fine-needle aspiration. The color Doppler appearance of each nodule was graded from 0 for no visible flow through 4 for extensive internal flow. The size, sonographic appearance, results of fine-needle aspiration, and surgical pathologic findings, if available, were recorded for each nodule. Results. There were 254 nodules sampled, of which 32 were malignant (all confirmed at surgery) and 177 were benign. Fourteen (43.8%) of the 32 malignant nodules were color type 4, compared with only 26 (14.7%) of the 177 benign nodules (P =.0004, Fisher exact test). Thirteen (40.1%) of the 32 malignant nodules were solid, as were 18 (10.2%) of the 177 benign nodules (P =.006, Fisher exact test). Among solid nodules, the prevalence of malignancy was greater when the nodule was hypervascular (13 [41.9%] of 31) than when the color type was less than 4 (11 [14.7%] of 77; P =.004, Fisher exact test). Conclusions. Solid hypervascular thyroid nodules have a high likelihood of malignancy (nearly 42% in our series). The color characteristics of a thyroid nodule, however, cannot be used to exclude malignancy, because 14% of solid nonhypervascular nodules were malignant. Key words: sonography, Doppler studies; thyroid, neoplasms; thyroid, sonography. Abbreviations FNA, fine-needle aspiration Received November 14, 2002, from the Departments of Radiology (M.C.F., C.B.B., P.M.D.), Medicine (Thyroid Division) (E.M.), and Pathology (E.S.C.), Harvard Medical School, Brigham and Women s Hospital, Boston, Massachusetts USA. Revision requested November 15, Revised manuscript accepted for publication November 15, Presented in part at the American Institute of Ultrasound in Medicine Annual Convention, Nashville, Tennessee, March 12, Address correspondence and reprint requests to Mary C. Frates, MD, Department of Radiology, Harvard Medical School, Brigham and Women s Hospital, 75 Francis St, Boston, MA USA. Thyroid nodules are extremely common, found at palpation in 4% to 7% of an asymptomatic population, 1 in 17% to 27% of cases at sonography, 2 4 and in 50% of cases at autopsy. 5 Although most thyroid nodules are benign, approximately 4% to 14% are malignant. 1,6 8 Several gray scale sonographic characteristics have been found to be highly suggestive of thyroid cancer, including microcalcifications and irregular margins, 9 but the role of color Doppler sonography in the evaluation of a thyroid nodule for malignancy has not been defined. Several reports have described no correlation between the presence of flow on color Doppler sonography and malignancy, particularly when color flow is considered as an isolated criterion. 9,10 Others have suggested that a pattern of either spotty intranodular flow 10 or hypervascular 2003 by the American Institute of Ultrasound in Medicine J Ultrasound Med 22: , /03/$3.50

2 Color Doppler Sonography of Malignancy of Thyroid Nodules central flow 7,11 13 on color Doppler sonography may be associated with malignancy. The purpose of this study was to determine whether color Doppler sonography can be used to diagnose or exclude malignancy in a thyroid nodule. Materials and Methods We performed color Doppler interrogation of all thyroid nodules undergoing fine-needle aspiration (FNA) in our department from October 2000 through June Imaging was performed with a variety of equipment (Sequoia, Acuson, a Siemens Company, Mountain View, CA; HDI 5000, Philips Medical Systems, Bothell, WA; and Elegra, Siemens AG, Munich, Germany), always with a high-frequency (7- to 15-MHz) small parts probe. Parameters were optimized in all cases to show slow flow. All color images were obtained before FNA. Color flow in each nodule was characterized without knowledge of the cytologic or pathologic findings by the consensus of at least 2 of 3 staff radiologists (M.C.F., C.B.B., and P.M.D.) as follows (Fig. 1): 0 for no visible flow, 1 for minimal internal flow without a peripheral ring, 2 for a peripheral ring of flow (defined as >25% of the nodule s circumference) but minimal or no internal flow, 3 for a peripheral ring of flow and a small-tomoderate amount of internal flow, and 4 for extensive internal flow with or without a peripheral ring. Nodules were measured in 3 dimensions, and a mean diameter was calculated. Gray scale sonographic characteristics for each nodule were described as solid, 1% to 24% cystic, 25% to 49% cystic, 50% to 74% cystic, 75% to 99% cystic, or 100% cystic. Sonographically guided FNA was performed on all nodules with a 25-gauge needle (3 or 4 passes per nodule), and specimens were processed by the ThinPrep technique (Cytyc Corporation, Boxborough, MA). All slides were interpreted by a cytopathologist. Results of FNA, surgical pathologic examination, or both were used to categorize all nodules as benign, malignant, or nondiagnostic. Nodules suggestive of follicular neoplasms at cytologic examination that showed uptake on a subsequent radioactive nuclide study (iodine 123 NaI or technetium Tc 99m pertechnetate) were considered to represent functioning follicular adenomas and were categorized as benign. Those suggestive of follicular neoplasms that did not show uptake proceeded to surgery. Statistical analysis was performed with the Student t test and Fisher exact test. Results There were 254 nodules included in our study. Of these, 177 were benign, 32 were malignant (all confirmed at surgical pathologic examination), and 45 were nondiagnostic. Nondiagnostic nodules (atypical cells or other abnormalities awaiting repeated FNA or surgery, insufficient cells, and patients lost to follow-up) were excluded from analysis, leaving 209 nodules to form the final study group, with a malignancy rate of 15% (32 of 209). The average diameter of the benign nodules was 20.7 ± 10.8 mm (mean ± SD; range, 7 57 mm), whereas the average diameter of the malignant nodules was 20.4 ± 10.3 mm (range, 7 46 mm). There was no significant difference in size between the 2 groups, (P =.88, Student t test). The most common sonographic characteristic for both benign and malignant nodules was a solid appearance (Table 1), seen in 84 (47.5%) of 177 benign nodules and 24 (75%) of 32 malignant nodules. Solid nodules were more likely to be malignant (24 [22.2%] of 108) than were those that were partially cystic (8 [7.9%] of 101; P =.006, Fisher exact test). Color flow characteristics of the nodules are shown in Table 2. Benign nodules tended to have lower color types than did malignant nodules. In particular, the frequency of hypervascularity (color type 4) was higher in malignant nodules (14 [43.8%] of 32) than in benign nodules (26 [14.7%] of 177; P =.0004, Fisher exact test). The color characteristics of the 108 solid nodules are reported in Table 3. Almost half (41.9%) of hypervascular (color type 4) solid nodules were malignant, compared with only 14.3% of nonhypervascular (color types 0 3) solid nodules (P =.004, Fisher exact test). Discussion Sonographic evaluation of the adult thyroid gland commonly shows nodules, most of which are benign. 1,8 Treatment of a thyroid nodule is usually dependent on its size and sonographic characteristics, with most nodules larger than 1.0 to 1.5 cm undergoing FNA or biopsy under sonographic guidance. It would be desirable to be able to identify with sonography which nod- 128 J Ultrasound Med 22: , 2003

3 Frates et al A B C D Figure 1. Classification of color Doppler patterns found in thyroid nodules. A, Color type 0. Sagittal image of a solid thyroid nodule shows no visible flow either within or around the periphery of the nodule. This nodule proved to be papillary cancer. B, Color type 1. Transverse image of a left solid thyroid nodule shows a small amount of internal flow without a peripheral ring. This nodule was benign at cytologic examination. C, Color type 2. Transverse image of a left thyroid nodule shows an extensive ring of flow around more than 25% of the periphery of the nodule but no internal flow. This nodule was benign at cytologic examination. D, Color type 3. Sagittal image of a solid thyroid nodule shows flow around more than 25% of the periphery of the nodule as well as a small amount of internal flow. This nodule was benign at cytologic examination. E, Color type 4. Transverse image of a left thyroid nodule shows extensive internal flow. A peripheral ring is also present. This nodule was found to be papillary cancer at pathologic examination. E J Ultrasound Med 22: ,

4 Color Doppler Sonography of Malignancy of Thyroid Nodules Table 1. Sonographic Characteristics of All 209 Nodules Characteristic Benign (177) Malignant (32) Solid* Cystic (at least partially) % % 99% % 74% % 49% % 24% 47 6 *P =.006, Fisher exact test (partially cystic versus solid). Table 2. Color Doppler Characteristics of All 209 Nodules Color Type Benign (177) Malignant (32) * *P =.0004, Fisher exact test (hypervascular [color type 4] versus nonhypervascular [color type <4]). Table 3. Color Characteristics of Solid Nodules Color Type Benign, n Malignant, n (%) Total, n 0 or (14.0) 43 2 or (14.7) 34 4* (41.9) 31 Total n indicates number of nodules. *P =.004, Fisher exact test (solid hypervascular [color type 4] versus solid nonhypervascular (color type <4]). ules are malignant and which are benign. Unfortunately, no sonographic criteria have been identified that can accurately distinguish benign from malignant nodules. This study examined the role of color Doppler sonography for detecting thyroid cancer. It represents one of the largest series of color Doppler analysis of thyroid nodules with cytologic or pathologic correlation. Our results show that both a solid nature and extensive internal blood flow are risk factors for malignancy. Indeed, the combination of hypervascularity and a solid nature had a high likelihood of malignancy (41.9%) in our series. Most studies evaluating the role of color Doppler sonography for the prediction of malignancy have limited the study population to nodules that are cold on radionuclide scans (i.e., nodules that do not take up a radioisotope). Several small series of cold nodules suggest that internal flow in a cold nodule is indicative of malignancy. 7,11,12 In a larger study of more than 100 patients with cold nodules, a hypervascular pattern alone was not a statistically significant finding for the prediction of malignancy. 9 In our study, scintigraphy was not performed routinely, and nodules were assessed only for size and sonographic and Doppler characteristics before biopsy. Our study shows that although the degree of vascularity as determined by color Doppler imaging differs in malignant and benign nodules, the role of color Doppler sonography in the evaluation and treatment of thyroid nodules is limited. In particular, malignant nodules cannot be distinguished reliably from benign nodules on the basis of the sonographic appearance (cystic versus solid), color Doppler characteristics, or both. More than 50% of the hypervascular solid nodules (those with color type 4) in our series were benign. In addition, more than 10% of the nonhypervascular solid nodules were malignant. These results confirm those of others. One large study that included 30 cases of papillary cancer found no significant difference in the color flow patterns of benign versus malignant nodules. 9 In another smaller series that included 7 malignancies, when color Doppler sonography was used in conjunction with gray scale sonography, it aided in the differentiation of neoplastic lesions from colloid nodules but was not sensitive enough to distinguish benign from malignant neoplasms. 14 Another large series, which compared color Doppler with power Doppler sonography, included more than 300 cold nodules (including 20 papillary cancers) and had results similar to ours, with a hypervascular color Doppler pattern common in, but not diagnostic of, papillary cancer. 13 The fact that we found a tendency for color Doppler characteristics to differ in malignant compared with benign nodules suggests one type of patient in which Doppler sonography might be useful: the patient with a large number of thyroid nodules who might otherwise be subjected to multiple FNAs. In such a patient, the presence of type 4 color vascularity in a solid nodule could direct the choice of the lesion to sample. 130 J Ultrasound Med 22: , 2003

5 Frates et al In conclusion, solid hypervascular thyroid nodules have a higher risk of malignancy than partially cystic or nonhypervascular lesions. However, the color Doppler characteristics of a thyroid nodule cannot be used to predict or exclude malignancy confidently, and FNA or biopsy is needed to determine the nature of the nodule. References 1. Mazzaferri E. Management of a solitary thyroid nodule. N Engl J Med 1993; 328: Carroll B. Asymptomatic thyroid nodules: incidental sonographic detection. AJR Am J Roentgenol 1982; 138: Kerr L. High-resolution thyroid ultrasound: the value of color Doppler. Ultrasound Q 1994; 12: Clark K, JJ C, Scola F. Color Doppler sonography: anatomic and physiologic assessment of the thyroid. J Clin Ultrasound 1995; 23: Cerbone G, Spiezia S, Colao A, et al. Power Doppler improves the diagnostic accuracy of color Doppler ultrasonography in cold thyroid nodules: follow-up results. Horm Res 1999; 52: Holden A. The role of colour and duplex Doppler ultrasound in the assessment of thyroid nodules. Australas Radiol 1995; 39: Woestyn J, Afschrift M, Schelstraete K, Vermeulen A. Demonstration of nodules in the normal thyroid by echography. Br J Radiol 1985; 58: Brander A, Viikinkoski V, Nickels J, Kivisaari L. Importance of thyroid abnormalities detected at US screening: a 5-year follow-up. Radiology 2000; 215: Mortenson J, Woolner L, Bennett W. Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol Metab 1955; 15: Cochand-Priollet B, Guillausseau P-J, Chagnon S, et al. The diagnostic value of fine-needle aspiration biopsy under ultrasonography in nonfunctional thyroid nodules: a prospective study comparing cytologic and histologic findings. Am J Med 1994; 97: Pacella C, Guglielmi R, Fabbrini R, et al. Papillary carcinoma in small hypoechoic thyroid nodules, predictive value of echo color Doppler evaluation: preliminary results. J Exp Clin Cancer Res 1998; 17: Marqusee E, Benson C, Frates M, et al. Usefulness of ultrasonography in the management of nodular thyroid disease. Ann Intern Med 2000; 133: Rago T, Vitti P, Chiovato S, et al. Role of conventional ultrasonography and color flow-doppler sonography in predicting malignancy in cold thyroid nodules. Eur J Endocrinol 1998; 138: Shimamoto K, Endo T, Ishigaki T, Sakuma S, Makino N. Thyroid nodules: evaluation with color Doppler ultrasonography. J Ultrasound Med 1993; 12: J Ultrasound Med 22: ,