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Jung Hyun Yoon, MD, PhD Hye Sun Lee, MS Eun-Kyung Kim, MD, PhD Hee Jung Moon, MD, PhD Jin Young Kwak, MD, PhD

Purpose:

To compare the malignancy rates and the effectiveness of the Thyroid Imaging Reporting and Data System (TIRADS) for risk stratification of nodules with nondiagnostic results classified before and after application of the Bethesda System for Reporting Thyroid Cytopathology.

Materials and Methods:

This retrospective study was approved by an institutional review board, with waiver of informed consent. A total of 763 patients with 790 thyroid nodules and nondiagnostic cytologic results were included (mean age 6 standard deviation, 52.3 years 6 11.5), 485 nodules from the preBethesda period (from March 2007 to December 2008) and 305 nodules from the post-Bethesda period (from May 2011 to May 2012). A TIRADS category was assigned to each thyroid nodule on the basis of the number of features that appeared suspicious for cancer at ultrasonography (US). Malignancy rates and TIRADS categories during the two periods were compared. Correlation between TIRADS category and malignancy risk between the two periods was evaluated and compared.

Results:

The malignancy rates of nodules with nondiagnostic cytologic results were not significantly different between the two periods (P = .148). Malignancy risk of TIRADS category 3, 4a, 4b, 4c, and 5 was 1.8%, 5.7%, 4.1%, 29.8%, and 16.7%, for the pre-Bethesda period, and 1.6%, 3.0%, 7.1%, 16.3%, and 25.0% for the post-Bethesda period, respectively. Nearperfect correlation was seen between the TIRADS category and malignancy risk in the post-Bethesda period (r = 0.961, P = .009), while no significant correlation was found in the pre-Bethesda period (r = 0.731, P = .161).

Conclusion:

Malignancy risk stratification with TIRADS was more effective for nodules with nondiagnostic cytologic results classified according to the Bethesda System. When these Bethesda-classified nodules with nondiagnostic results are evaluated as TIRADS category 3 or 4a, they may be treated conservatively with follow-up US, but when other cytologic classifications are applied, follow-up US and fineneedle aspiration must be considered for nodules showing one or more features suspicious for cancer at US.

1

 From the Department of Radiology, Severance Hospital, Research Institute of Radiological Science (J.H.Y., E.K.K., H.J.M., J.Y.K.), and Biostastistics Collaboration Unit, Medical Research Center (H.S.L.), Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, 120-752 Seoul, Korea. Received September 30, 2014; revision requested November 18; revision received December 22; accepted January 8, 2015; final version accepted January 15. Address correspondence to J.Y.K. (e-mail: [email protected]).

 RSNA, 2015

q

 RSNA, 2015

q

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1

Original Research  n  Ultrasonography

Thyroid Nodules: Nondiagnostic Cytologic Results according to Thyroid Imaging Reporting and Data System before and after Application of the Bethesda System1

ULTRASONOGRAPHY: Thyroid Nodules and Nondiagnostic Cytologic Results

F

ine-needle aspiration (FNA) under ultrasonographic (US) guidance is considered the diagnostic procedure of choice for treatment of thyroid nodules (1–4) and has been proven efficient, accurate, inexpensive, and safe for the differential diagnosis of thyroid nodules. In spite of its many strong points, FNA, even with US guidance, has inherent diagnostic limitations, such as nondiagnostic, inadequate, or unsatisfactory results. As with the many terms used in describing this cytologic category, the criteria used to determine specimen adequacy vary among cytopathologists and institutions, and the meaning of nondiagnostic cytologic results may be used broadly to describe specimens showing scanty follicular cells or aspirates that are suboptimally suggestive of malignancy. Accordingly, the reported incidence of nondiagnostic cytologic results varies from 3% to 22% (2,4–8) and shows a broad range of malignancy rates from 4% to 33%. Thus, this creates confusion in the treatment of patients, with approximately 10%– 30% of patients undergoing diagnostic lobectomy for a benign diagnosis (4,9). The Bethesda System for Reporting Thyroid Cytopathology (10) was created and introduced in the year 2009 to help overcome this inconsistency in the hope that providing cytologic reports with uniform terminology among pathologists and laboratories would

Advances in Knowledge nn Malignancy risks of Thyroid Imaging Reporting and Data System (TIRADS) categories 3, 4a, 4b, 4c, and 5 nodules were 1.8%, 5.7%, 4.1%, 29.8%, and 16.7% for the pre-Bethesda period and 1.6%, 3.0%, 7.1%, 16.3%, and 25.0% for the post-Bethesda period, respectively. nn Near-perfect correlation was seen between the TIRADS category and malignancy risk in the post-Bethesda period (r = 0.961, P = .009), but no significant correlation was found in the preBethesda period (r = 0.731, P = .161). 2

Yoon et al

improve communication between pathologists and clinicians, surgeons, or radiologists who are involved in FNA procedures. The Bethesda system is not only limited to terminology. It also provides data on the suitable proportion of nodules of each cytologic category that should be observed in the laboratory along with advisable malignancy risks and management recommendations for each category. According to the Bethesda System, inadequate cytologic samples are reported as nondiagnostic or unsatisfactory, and this classification should be applied to samples that are unsatisfactory due to obscuring blood, thick smears, air-drying artifacts, or an inadequate number of follicular cells for interpretation. The advised malignancy risk of nondiagnostic cytologic results is 1%–4% (10), and repeat FNA under US guidance is recommended. In addition, the Bethesda System has set several exceptions to the numeric requirement of nondiagnostic cytologic results (ie, sparsely cellular specimens with abundant colloid). When a specific diagnosis such as lymphocytic thyroiditis can be given or if atypia is present, these should be categorized into diagnostic cytologic categories (10). These exceptions may have a considerable effect on both the frequency and outcome of nondiagnostic cytologic results compared with results before the application of the Bethesda System. Also, because US features have been well documented already for the prediction of malignancy among thyroid nodules, many guidelines recommend applying

US for nodule characterization (11–13), In 2011, Kwak et al (14) proposed the Thyroid Imaging Reporting and Data System (TIRADS), which is a well-structured reporting system that involves the use of US of the thyroid for risk stratification (15). Although authors of several studies have evaluated the efficacy of the Bethesda System for reporting thyroid FNA cytology (1,4,5,9,16,17), there have been no studies in which investigators compared the US features of nodules with nondiagnostic cytologic results before and after the application of the Bethesda System. In this study, we compared the malignancy rates and the effectiveness of the TIRADS for risk stratification of nodules with nondiagnostic results classified before and after application of the Bethesda System for Reporting Thyroid Cytopathology.

Materials and Methods This study was retrospective and was approved by the institutional review board of Severance Hospital, Seoul, Korea. Neither patient approval nor informed consent was required for retrospective review of medical records or US images.

Patients The use of the Bethesda System in thyroid cytopathologic reports started in December 2009 at our institution (a

Published online before print 10.1148/radiol.15142308  Content code: Radiology 2015; 000:1–9

Implication for Patient Care nn Nodules with nondiagnostic results of evaluation with the Bethesda System that are assessed as TIRADS category 3 or 4a may be managed conservatively with follow-up US, but when other cytologic classifications are applied, follow-up US and fine-needle aspiration must be considered in nodules showing one or more features suspicious for cancer at US.

Abbreviations: FNA = fine-needle aspiration TIRADS = Thyroid Imaging Reporting and Data System Author contributions: Guarantor of integrity of entire study, J.Y.K.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, J.H.Y.; clinical studies, J.H.Y., E.K.K., J.Y.K.; statistical analysis, J.H.Y., H.S.L.; and manuscript editing, J.H.Y., H.S.L., E.K.K., H.J.M. Conflicts of interest are listed at the end of this article.

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ULTRASONOGRAPHY: Thyroid Nodules and Nondiagnostic Cytologic Results

referral center), and since then, this reporting system has been used consistently. We performed a retrospective review of our institutional database for all thyroid US-guided FNA procedures performed in nodules measuring larger than 5 mm during the periods of March 2007 to December 2008 (ie, the preBethesda period) and May 2011 to May 2012 (ie, the post-Bethesda period). US-guided FNA was used for 9067 thyroid nodules during these periods. Among them, 827 of 5441 (15.2%) and 506 of 3626 (14.0%) nodules were given nondiagnostic cytologic results during the pre- and post-Bethesda periods, respectively. Thyroid nodules with the following conditions were included: (a) nodules on which surgery had been performed, (b) nodules with definitive benign or malignant cytologic results at follow-up US-guided FNA, (c) nodules with nondiagnostic cytologic results at follow-up US-guided FNA that showed no significant change, defined as no change or increase of less than 3 mm in maximum diameter or less than 15% of initial volume (16), or decrease in size at follow-up US performed at least 1 year after nondiagnostic results, and (d) nodules that showed no change in size or decrease in size at follow-up US performed at least 1 year after initial nondiagnostic cytologic results. Finally, 790 thyroid nodules in 763 patients with nondiagnostic cytologic results were included in this study, with 485 nodules in 477 patients from the pre-Bethesda period and 305 nodules in 286 patients from the post-Bethesda period (Fig 1). Mean 6 standard deviation age of the 763 patients included in this study was 52.3 years 6 11.5 (range, 19–81 years). Mean size of the 790 thyroid nodules was 17.6 mm 6 13.4 (range, 5–80 mm). Mean follow-up interval from the initial US-guided FNA to the last follow-up US of thyroid nodules on which surgery had not been performed (n = 659) was 24.1 months (range, 12–30.7 months). Of the 790 nodules included in this study, 366 nodules also were included in a previously published study in which the authors evaluated the factors affecting

inadequate sampling at US-guided FNA (17), 119 were included in a study of the US features that are more suggestive of malignancy among nodules with initial nondiagnostic cytologic results after USguided FNA (2), and 184 were used in a study to determine whether quantitative measurement of vascularity at Doppler US is a predicting factor for lymph node metastasis in patients with papillary thyroid microcarcinoma (18).

US and US-guided FNA Procedures US examinations were performed by using a 7–15-MHz linear-array transducer (HDI5000; Philips Medical Systems, Bothell, Wash), an 8–15-MHz lineararray transducer (Acuson Sequoia; Siemens Medical Solutions, Mountain View, Calif), or a 5–12-MHz lineararray transducer (iU22; Philips Medical Systems). All images obtained with an HDI5000 or iU22 machine were compound images. Real-time US and subsequent US-guided FNA were performed by one of 13 radiologists (three faculty members who consistently performed US-guided FNA during both periods, two fellows during the pre-Bethesda period, and eight fellows during the postBethesda period, with 1–15 years of experience in thyroid imaging). US-guided FNA was performed in thyroid nodules showing features at US that were suspicious for cancer or on the largest mass when none of the multiple thyroid nodules observed showed any US features suspicious for cancer. US features of each thyroid nodule were described according to the following categories: internal components, echogenicity, margin, calcifications, and shape (11). Internal components were further classified into solid, mainly solid (solid contents consisting of more than 50%), and mainly cystic (solid contents consisting of less than 50%). Echogenicity was classified into hyper- or isoechoic (nodules showing hyper- to isoechogenicity when compared with the surrounding thyroid parenchyma), hypoechoic (nodules showing hypoechogenicity compared with the surrounding thyroid parenchyma), and markedly hypoechoic (nodules showing hypoechogenicity compared

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Yoon et al

with the adjacent strap muscle). Margins were classified as circumscribed or noncircumscribed (ie, microlobulated or irregular margins). The presence of calcifications was classified as no calcifications, microcalcifications or mixed calcifications, or macrocalcifications including eggshell calcifications. Shape was classified as parallel or nonparallel (greater in the anteroposterior dimension than in the transverse dimension, or taller than they were wide). Of these features, the US features that defined malignancy were marked hypoechogenicity, noncircumscribed margins, microcalcifications or mixed calcifications, and nonparallel shape on the basis of published criteria (11).

Cytologic Interpretation Thyroid nodules showing one or more features suspicious for cancer at US or the largest among multiple thyroid nodules showing benign features were subjected to US-guided FNA. US-guided FNA was performed at least twice in each thyroid nodule by using a 23-gauge needle attached to a 2-mL disposable syringe without an aspirator. Local anesthesia was not routinely used. Aspirated material was expelled on glass slides and immediately placed in 95% ethanol for Papanicolau staining. The remaining material in the syringe was rinsed in saline solution for cell block processing. Cytopathologists were not present during procedures, and additional staining was performed on a case-by-case basis at the cytopathologists’ request. One of the five cytopathologists specializing in thyroid pathology interpreted the cytologic slides. Until December 2009, cytologic reports at our institution were divided into the following five categories (19,20): (a) malignancy, specimen showing abundant cells with unequivocal cytologic features of malignancy; (b) suspicious for papillary thyroid carcinoma, specimen exhibiting cytologic atypia, but insufficient cellularity to make a definite diagnosis of malignancy; (c) indeterminate, including follicular neoplasm or Hürthle cell neoplasm, specimen showing cytologic findings of monotonous cellular population and scanty colloid, lacking papillary carcinoma features; (d) 3

ULTRASONOGRAPHY: Thyroid Nodules and Nondiagnostic Cytologic Results

Yoon et al

Figure 1

Figure 1:  Flow diagram shows selection of thyroid nodules in study population. ND = nondiagnostic result.

benign, including colloid nodules, nodular hyperplasia, lymphocytic thyroditis, Graves’ disease, and postpartum thyroiditis; and (e) inadequate, specimen showing less than six groupings of wellpreserved thyroid cells, each consisting of less than 10 cells per group (2). From December 2009, cytologic reports from US-guided FNA of thyroid nodules were compiled on the basis of the six categories of the Bethesda System for Reporting Thyroid Cytopathology (10).

Data and Statistical Analysis Histopathologic results from surgery or follow-up US-guided FNA were considered the reference standard. Nodules diagnosed as benign at follow-up US-guided FNA showing stable or decreased size at follow-up US examinations performed at an interval of more than 12 months were considered benign. Nodules diagnosed as malignant at follow-up US-guided FNA on which surgery had not been performed were considered malignant. For US assessment, a TIRADS category was assigned to each thyroid nodule retrospectively by one radiologist (J.H.Y., with 6 years of experience in thyroid imaging) on the basis of the number of features suspicious for cancer 4

at US by using the following categories: solidity, hypoechogenicity or markedly hypoechogenicity, microlobulated or irregular margins, microcalcifications, and shape that is taller than it is wide (14). Thyroid nodules without any features suspicious for cancer at US were classified as TIRADS category 3. Nodules showing one, two, three or four, or five features suspicious for cancer at US were classified as category 4a, 4b, 4c, or 5, respectively (Fig 2). Statistical analysis was performed at both the subject and the nodule level in the comparison of demographic and imaging features of the nodules with nondiagnostic results during the pre- and post-Bethesda periods. At subject-level analysis, an independent two-sample t test was used to compare continuous variables, while the x2 test or Fisher exact test was used for comparing categorical variables. At nodule-level analysis, logistic regression for clustered data (generalized estimating equations method) was used to compare the demographic and imaging features. Estimated malignancy rates and standard errors for US features and TIRADS final assessment categories were calculated by using the generalized estimating equations method. The Pearson

correlation test was used to evaluate the relationship between the TIRADS assessment category and malignancy rate, ie, the overall percentage of malignant nodules in each category during the two periods, and the correlation between the malignancy rate of each TIRADS category calculated in the two periods to the malignancy rate of each TIRADS category reported by Kwak et al (14) (reference value). The sum of squared residual value was calculated to see the differences in malignancy rates for TIRADS categories between pre- and post-Bethesda periods compared with the reference value. Analyses were performed by using software (PASW version 18; IBM Corporation, Somers, NY or SAS version 9.2; SAS, Cary, NC). All tests were two sided, and P values of less than .05 were considered to indicate a significant difference.

Results The malignancy rate of the thyroid nodules with nondiagnostic cytologic results from the post-Bethesda period (26 of 305 [8.5%]) was lower than that from the pre-Bethesda period (57 of 485 [11.8%]), but the difference was not significant (P = .150). Table 1

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ULTRASONOGRAPHY: Thyroid Nodules and Nondiagnostic Cytologic Results

Yoon et al

Figure 2

Figure 2:  Representative US images of thyroid nodules of each TIRADS category. (a) TIRADS category 3: image shows a mixed solid and cystic thyroid nodule without any US features suspicious for cancer. (b) TIRADS category 4a: image shows a solid, isoechoic nodule with well-defined margins. (c) TIRADS category 4b: image shows a solid, hypoechoic nodule with well-defined margins. (d) TIRADS category 4c: image shows a solid, hypoechoic nodule with irregular margins (arrows) and nonparallel shape. (e) TIRADS category 5: image shows a solid, markedly hypoechoic nodule with irregular margins, nonparallel shape and mixed microcalcifications (arrows), and macrocalcifications.

shows the demographic features of the patients and the thyroid nodules. Mean age was older in patients from the post-Bethesda period than from the pre-Bethesda period (54.1 years 6 11.3 vs 51.0 years 6 11.5, respectively [P , .001]). Mean tumor size was not significantly different between the two periods, 16.9 mm 6 13.1 (range, 5–80 mm) in the pre-Bethesda period and 18.8 mm 6 13.8 (range, 5–61 mm) in post-Bethesda period (P = .071). More conservative approaches such as follow-up US for management of thyroid nodules with nondiagnostic cytologic results were used instead of US-guided FNA or surgery in the post-Bethesda period (P , .001). The mean follow-up interval from the initial US-guided FNA to the last follow-up US in nodules on which surgery had not been performed was 25.2 months 6 21.8 for the pre-Bethesda period and 15.9 months 6 9.1 for the post-Bethesda period. Table 2 summarizes the comparison of US features of the thyroid nodules

with nondiagnostic cytologic results from the two periods. Malignant nodules had significantly higher rates of solid composition, hypoechogenicity or marked hypoechogenicity, microlobulated or irregular margins, and microcalcifications (all P , .05). Among the 485 thyroid nodules from the pre-Bethesda period, the malignancy risk of TIRADS category 3, 4a, 4b, 4c, and 5 nodules was 1.8% (two of 111), 5.7% (seven of 123), 4.1% (five of 99), 29.8% (42 of 141), and 16.7% (two of 12), respectively. Of the 305 thyroid nodules from the post-Bethesda period, the malignancy rate of category 3, 4a, 4b, 4c, and 5 nodules was 1.6% (one of 63), 3.0% (two of 66), 7.1% (five of 70), 16.3% (16 of 98), and 25.0% (two of eight), respectively. Near-perfect correlation was seen between the TIRADS category and malignancy risk in the postBethesda period (r = 0.961, P = .009, Fig 3). Correlation between the TIRADS category and malignancy risk of nodules with nondiagnostic results from the

Radiology: Volume 000: Number 0—   2015  n  radiology.rsna.org

pre-Bethesda period was not statistically significant (r = 0.731, P = .161). Table 3 shows the sum of squared residual for each TIRADS category between the pre- and post-Bethesda period to the reference value. Differences in the sum of squared residuals were smaller for the post-Bethesda period than for the pre-Bethesda period, and for each individual TIRADS category. Near-perfect correlation was seen between the malignancy rates of TIRADS categories in the post-Bethesda period and the reported reference value (r = 0.986, P = .002). Correlation between the malignancy risk of the TIRADS categories of the pre-Bethesda period and the reported reference value was not statistically significant (r = 0.665, P = .221).

Discussion The malignancy rate of nondiagnostic cytologic results from the pre-Bethesda period was comparably higher than that 5

ULTRASONOGRAPHY: Thyroid Nodules and Nondiagnostic Cytologic Results

Yoon et al

Table 1 Demographics of Patients and Thyroid Nodules Pre-Bethesda Period Demographic Variable No. of patients No. of nodules Subject level  Sex   Male   Female   Age (y)‡ Nodule level   Size (mm) ‡   Follow-up method   Surgery   US-guided FNA   US   Follow-up duration (mo) ‡

Benign

Malignant

Total

421 428

56 57

477 485

75 (17.7) 346 (82.3) 51.0 6 11.5

11 (19.6) 45 (80.4) 50.7 6 11.6

86 (18.0) 391 (82.0) 51.0 6 11.5

17.6 6 13.2

11.4 6 10.7

16.9 6 13.1

... ... ... ...

... ... ... ...

85 (17.5) 169 (34.9) 231 (47.6) 25.2 6 21.8

Post-Bethesda Period P Value*

P Value*

Benign

Malignant

Total

261 279

25 26

286 305 .602

.502

.979

61 (23.4) 200 (76.6) 54.3 6 11.4

7 (26.9) 18 (73.1) 51.7 6 11.0

67 (23.4) 219 (76.6) 54.1 6 11.3

.280

,.001

,.001

19.3 6 14.1

13.0 6 8.1

18.8 6 13.8

.001

.071 ,.001

... ... ... ...

... ... ... ...

46 (15.1) 69 (22.6) 190 (62.3) 15.9 6 9.1

.176

P Value†

,.001

Note.—Data in parentheses are percentages. * P value is a comparison between benign and malignant nodules during each period. †

P value is a comparison between pre-Bethesda and post-Bethesda periods.

‡

Data are means 6 standard deviation.

from the post-Bethesda period (11.8% vs 8.5%, respectively), although this difference was not statistically significant. As we mentioned previously, during the pre-Bethesda period, cytologic diagnosis at our institution was based on a five-tier classification system that differs from the Bethesda System in that the designation “atypia of undetermined significance or follicular lesion of undetermined significance” was not used (19,20). Some lesions that may have been categorized as atypia or follicular lesion of undetermined significance during the post-Bethesda period may have been considered to show nondiagnostic cytologic results during the pre-Bethesda period, contributing to the higher malignancy rate. Although authoritative guidelines commonly recommend repeat US-guided FNA in nodules with nondiagnostic cytologic results, the malignancy rate for nondiagnostic cytologic results is reported to be 1%–4%, similar to the 3% recommended for benign cytologic results for which clinical follow-up is recommended on the basis of the Bethesda System (10). A recent study proposed that nondiagnostic cytologic 6

results from an appropriately performed initial FNA may indicate benignity, which may reassure practitioners that imaging follow-up can be considered over follow-up US-guided FNA (21). Imaging features also may provide practitioners with the confidence to consider conservative follow-up for these nodules, because nodules with nondiagnostic cytologic results and no features suspicious for cancer at US also had significantly lower malignancy rates compared with nodules with features suspicious for cancer at US (2,22–27). In a recent study (24) in which researchers evaluated the performance of TIRADS as developed by Kwak et al (14) in thyroid nodules with nondiagnostic results that were observed during the post-Bethesda period, low malignancy rates were reported in nodules with nondiagnostic results that were classified as TIRADS 3 (0.8%) or 4a (1.8%), and therefore, these may be followed up with US examinations. In our study, the malignancy rate of category 3 nodules was 1.8% for the pre-Bethesda period and 1.6% for the post-Bethesda period,

which were both within the range of the 3% malignancy risk of benign cytologic results considered suitable for clinical follow-up according to the Bethesda System (10). However, the malignancy rate of category 4a nodules for the pre-Bethesda period was 5.7%, which was above the accepted range for conservative follow-up, and that for the post-Bethesda period was 3.0%. This high malignancy rate may have been due to the presence of atypical cells in specimens that contained insufficient cell counts for diagnosis; these specimens may have been classified as atypia or follicular lesion of undetermined significance during the post-Bethesda period. Although further prospective studies are needed to justify our results, we believe that conservative follow-up with US examinations may be considered in nodules with nondiagnostic cytologic results after the application of the Bethesda System that are assessed as category 3 or 4a on the basis of TIRADS. In addition, we evaluated whether the TIRADS can be used effectively to stratify malignancy risk among thyroid nodules with nondiagnostic cytologic

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53 (93.0) 1 (1.8) 3 (5.2)

10 (17.5) 38 (66.7) 9 (15.8)

16 (28.1) 41 (71.9)

24 (42.1) 16 (28.1) 17 (29.8)

30 (52.6) 27 (47.4)

2 (3.5) 7 (12.3) 4 (7.0) 42 (73.7) 2 (3.5)

246 (57.5) 88 (20.5) 94 (22.0)

189 (44.2) 212 (49.5) 27 (6.3)

316 (73.8) 112 (26.2)

308 (72.0) 81 (18.9) 39 (9.1)

365 (85.3) 63 (14.7)

109 (25.5) 116 (27.1) 94 (22.0) 99 (23.1) 10 (2.3)

Malignant (n = 57)

1.8 (1.3) 5.7 (2.1) 4.1 (2.0) 29.8 (3.9) 16.7 (10.8)

7.6 (1.3) 30.0 (4.9)

7.2 (1.4) 16.5 (16.5) 30.4 (6.2)

4.8 (1.2) 26.8 (3.6)

5.0 (1.5) 15.2 (2.3) 25.0 (7.2)

17.7 (2.2) 1.1 (1.1) 3.1 (1.8)

11.8 (1.5)

P value is comparison between benign and malignant nodules in each period.

P value is comparison between the pre-Bethesda and post-Bethesda periods.

P value is comparison between the pre-Bethesda and post-Bethesda periods with logistic regression for clustered data.

‡

§

111 (22.8) 123 (25.4) 98 (20.2) 141 (29.1) 12 (2.5)

395 (81.4) 90 (18.6)

332 (68.5) 97 (20.0) 56 (11.5)

332 (68.5) 113 (23.3)

199 (41.0) 250 (51.5) 36 (7.5)

299 (61.6) 89 (18.4) 97 (20.0)

†

* Data are standard error, with percentage in parentheses.

, .001

, .001

, .001

, .001

, .001

, .001

P Value†

Benign (n = 279)

Malignant (n = 26)

62 (22.2) 64 (22.9) 65 (23.3) 82 (29.4) 6 (2.2)

242 (86.7) 37 (13.3)

195 (69.9) 39 (14.0) 45 (16.1)

211 (75.6) 68 (24.4)

100 (35.9) 170 (60.9) 9 (3.2)

176 (63.1) 50 (17.9) 53 (19.0)

1 (3.8) 2 (7.7) 5 (19.2) 16 (61.5) 2 (7.7)

19 (73.1) 7 (26.9)

11 (42.3) 6 (23.1) 9 (34.6)

11 (42.3) 15 (57.7)

1 (3.9) 22 (84.6) 3 (11.5)

22 (84.6) 3 (11.5) 1 (3.8)

1.6 (1.6) 3.0 (2.1) 7.1 (3.6) 16.3 (3.8) 25.0 (15.3)

7.3 (1.7) 15.9 (5.5)

5.3 (1.7) 13.3 (5.1) 16.7 (5.1)

5.0 (1.6) 18.1 (4.3)

1.0 (1.0) 11.5 (2.4) 25.0 (12.5)

11.1 (2.3) 5.7 (3.2) 1.9 (1.8)

8.5 (1.7)

Estimated Malignancy Rate*

Total (n = 485)

Estimated Malignancy Rate*

Note.—Unless otherwise indicated, data in parentheses are percentages.

Total Composition  Solid   Mainly solid   Mainly cystic Echogenicity   Hyper- to isoechoic  Hypoechoic   Markedly hypoechoic Margin   Well defined   Microlobulated or  irregular Calcifications  None  Macro  Micro Shape  Parallel  Nonparallel TIRADS category  3  4a  4b  4c  5

US Feature

Benign (n = 428)

Post-Bethesda Period

Pre-Bethesda Period

US Features of Thyroid Nodules with the Pre- and Post-Bethesda System

Table 2

.003

.136

.050

.004

, .001

.008

P Value†

63 (20.7) 66 (21.6) 70 (23.0) 98 (32.1) 8 (2.6)

261 (85.6) 44 (14.4)

206 (67.5) 45 (14.8) 54 (17.7)

222 (72.8) 83 (27.2)

101 (33.1) 192 (63.0) 12 (3.9)

198 (64.9) 53 (17.4) 54 (17.7)

Total (n = 305)

.615

.128

.023

.196

.003

.148 .641

P Value‡

.140

.072

.363

.132

.961

.057

P Value§

ULTRASONOGRAPHY: Thyroid Nodules and Nondiagnostic Cytologic Results Yoon et al

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ULTRASONOGRAPHY: Thyroid Nodules and Nondiagnostic Cytologic Results

results and to compare malignancy risk between pre- and post-Bethesda periods. Results of our study showed near-perfect correlation of TIRADS categories to malignancy risk in the post-Bethesda period, but correlation in the pre-Bethesda period was not statistically significant. Malignancy rates calculated for the TIRADS categories in the two periods showed that values for the post-Bethesda period approximated the reference value reported by Kwak et al (14), supporting the use of a systematic diagnostic approach including both imaging features

Yoon et al

and the Bethesda System in the diagnosis of thyroid nodules. Our study had several limitations. First, this study was of retrospective design, and selection bias may have occurred in patient inclusion. Of the 1333 nodules with nondiagnostic cytologic results from the two periods, 488 (36.6%) were excluded because of loss to follow-up after initial nondiagnostic cytologic results. Also, 54 (4.1%) nodules that showed increased size at follow-up US that was not pathologically confirmed were excluded, which may have altered the results of our study.

Figure 3

Figure 3:  Line graph shows correlation of TIRADS category with malignancy risk of thyroid nodules in pre- and post-Bethesda periods. Near-perfect correlation was seen in post-Bethesda period (r = 0.961, P , .001), while correlation between TIRADS malignancy risk of nodules with nondiagnostic results from pre-Bethesda period was not statistically significant (r = 0.731, P = .104).

In addition, although this study was of a retrospective design, consecutive patients who had been scheduled for US examinations at our institution during the study period had been included, therefore, the study design may have had little effect on our results. Second, thyroid nodules with initial nondiagnostic cytologic results that had not been subjected to follow-up US-guided FNA or surgery were included. Although those with only stable or decreased size at follow-up US examinations were included, all of these nodules were considered benign despite the possibility that histopathologic results from US-guided FNA or surgery might have proven otherwise. Third, five cytopathologists were involved in interpreting the cytologic results in our study. Similarly, US results recorded by 13 radiologists were used in the analysis of US features. Interobserver variability, which is known to exist among cytopathologists (28) and radiologists (29), was not considered. Last, the retrospective design necessarily confounded the comparison of the preand post-Bethesda groups because the time since the pre-Bethesda period was from March 2007 to December 2008, but the post-Bethesda period was from May 2011 to May 2012. As a result, the observed group difference may be due, at least partially, to the effect of any aspect of clinical practice or image evaluation that changed with time. In conclusion, malignancy risk stratification by using TIRADS was

Table 3 Sum of Squared Residuals for the Pre- and Post-Bethesda Period TIRADS 3 4a 4b 4c* 5

∑ (y 2 y ) i

Reference Value ( y ) (14)

Pre-Bethesda Period ( y1 )

Post-Bethesda Period ( y2)

y 2 y1

y 2 y2

( y 2 y1)2

( y 2 y2)2

1.7 3.3 6.2 44.4–72.4 87.5 ...

1.8 5.7 4.1 29.8 16.7 ...

1.6 3 7.1 16.3 25 ...

20.1 22.4 2.1 14.6 70.8 ...

0.1 0.3 20.9 28.1 62.5 ...

0.01 5.76 4.41 213.16 5012.64 5235.98

0.01 0.09 0.81 789.61 3906.25 4696.77

* Minimum value for category 4c was used to compare pre- and post-Bethesda periods to reference value

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ULTRASONOGRAPHY: Thyroid Nodules and Nondiagnostic Cytologic Results

more effective in nodules with nondiagnostic results classified according to the Bethesda System. Nodules with nondiagnostic results according to the Bethesda System that were assessed as TIRADS category 3 or 4a may be managed conservatively with follow-up US, but when other cytologic classifications are applied, follow-up US-guided FNA must be considered in nodules showing one or more features suspicious for cancer at US. Disclosures of Conflicts of Interest: J.H.Y. disclosed no relevant relationships. H.S.L. disclosed no relevant relationships. E.K.K. disclosed no relevant relationships. H.J.M. disclosed no relevant relationships. J.Y.K. disclosed no relevant relationships.

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