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To identify demographic and ultrasonographic (US) features associated with malignancy after initially nondiagnostic results of fine-needle aspiration (FNA) to help clarify the role of repeat FNA, surgical excision, or serial US in these nodules.

Materials and Methods:

This study was HIPAA compliant and institutional review board approved; informed consent was waived. Thyroid nodules (n = 5349) that underwent US-guided FNA in 2004–2012 were identified; 393 were single nodules with nondiagnostic FNA results but adequate cytologic, surgical, or US follow-up. Demographic information and diameters and volume at US at first biopsy were modeled with malignancy as outcome through medical record review. Exact logistic regression was used to model malignancy outcomes, demographic comparisons with age were made (Student t test, Satterthwaite test), and proportion confidence intervals (CIs) were estimated (Clopper-Pearson method).


Of 393 nodules with initially nondiagnostic results, nine malignancies (2.3%) were subsequently diagnosed with repeat FNA (n = 2, 0.5%) or surgical pathologic examination (n = 7, 1.8%), 330 (84.0%) were benign, and 54 (13.7%) were stable or decreased in size at serial US (mean follow-up, 3.0 years; median, 2.5 years; range, 1.0–7.8 years). Patients with malignancies were significantly older (mean age, 62.7 years; median, 64 years; range, 47–77 years) than those without (mean age, 55.4 years; median, 57 years; range, 12–94 years; P = .0392). Odds of malignancy were 4.2 times higher for men versus women (P = .045) and increased significantly for each 1-cm increase in anteroposterior, minimum, and mean nodule diameter (1.78, 2.10, and 1.96, respectively). In 393 nodules, no malignancies were detected in cystic or spongiform nodules (both, n = 11, 2.8%; 95% CI: 1.4%, 5.0%), nodules with eggshell calcifications (n = 9, 2.3%; 95% CI: 1.1%, 4.3%), or indeterminate echogenic foci (n = 39, 9.9%; 95% CI: 7.2%, 13.3%).


Very few malignancies were diagnosed with repeat FNA following nondiagnostic FNA results (two of 336, 0.6%); therefore, clinical and US follow-up may be more appropriate than repeat FNA following nondiagnostic biopsy results.


 From the Department of Diagnostic Imaging (T.J.T.A., M.K.A., D.J.G., J.J.C., M.D.B.) and Lifespan Biostatistics Core (G.L.B.), Rhode Island Hospital, 593 Eddy St, Providence, RI 02903. Received September 10, 2013; revision requested October 23; final revision received January 7, 2014; accepted January 31; final version accepted February 28. Address correspondence to M.D.B. (e-mail: [email protected]).

 RSNA, 2014


 RSNA, 2014


Radiology: Volume 272: Number 3—September 2014  n


and Neck Imaging

Thomas J. T. Anderson, MD Michael K. Atalay, MD David J. Grand, MD Grayson L. Baird, MS John J. Cronan, MD Michael D. Beland, MD

Original Research  n  Head

Management of Nodules with Initially Nondiagnostic Results of Thyroid Fine-Needle Aspiration: Can We Avoid Repeat Biopsy?1

HEAD AND NECK IMAGING: Repeat Biopsy after Nondiagnostic Thyroid Fine-Needle Aspiration?


hyroid nodules are common and typically benign. While an estimated 4% of the population has a thyroid nodule detectable by palpation (1), ultrasonography (US) can depict nodules in 35%–68% of asymptomatic patients (2–4), and postmortem studies suggest that the true lifetime prevalence of thyroid nodules may be closer to 60%–70% (5,6). Approximately 5%–15% of thyroid nodules are malignant, but US cannot reliably differentiate cancers from benign nodules (3,7). As such, clinical guidelines recommend fine-needle aspiration (FNA) of nodules with a maximal diameter greater than 1–1.5 cm and of nodules that are smaller with US features of concern, such as taller-than-wide morphologic characteristics, solid hypoechoic echotexture, irregular border, central vascularity, microcalcifications, or abnormal cervical lymphadenopathy (8–10). The reported diagnostic yield of thyroid FNA varies from 80% to 99%, with an average of 85% (11–15). More important, a nondiagnostic thyroid FNA result is a common clinical challenge. Current guidelines recommend repeat FNA after a nondiagnostic result (10). However, researchers in a recent study (16) suggested that the incidence of malignancy at repeat FNA may in fact be substantially lower than the malignancy rate of initial biopsy. While diagnostic rates can be improved with on-site cytopathologic analysis

Advances in Knowledge nn Malignancy rate following nondiagnostic thyroid fine-needle aspiration (FNA) results was 2.3% (nine of 393); 66.7% (six of nine) of the detected malignancies were papillary carcinomas. nn Repeat FNA allowed diagnosis of very few malignancies (two of 336, 0.6%) and had a false-positive rate of 4.9% (16 of 329) and a positive predictive value of 11.1% (two of 18); 62.3% of nodules (245 of 393) were eventually diagnosed as benign with subsequent FNA. 778

(17,18), cytopathologic analysis is cumbersome and inefficient, particularly at high-volume centers (19,20). Alternatives to repeat biopsy include follow-up US examinations to monitor stability or surgical intervention in the form of partial or total thyroidectomy. The purpose of this study was to identify demographic and US features of thyroid nodules that may be predictive of malignancy after initially nondiagnostic FNA results to help clarify the role of repeat FNA, surgical excision, or serial US in these nodules.

Materials and Methods This study was Health Insurance Portability and Accountability Act compliant and received institutional review board approval; informed consent was waived. Patients were referred to our hospital-based US suite for the evaluation of thyroid nodules that had been discovered with physical examination or were noted incidentally during a prior imaging study.

Data Collection Through a search of our Department of Pathology database, we identified 5349 nodules that underwent US-guided FNA in our Department of Radiology between 2004 and 2012. Of these, 776 (14.5%) nodules were reported as having nondiagnostic results. We excluded 383 (49.4%) of these nodules from our analyses because they had (a) no follow-up or US follow-up of less than 1 year (281 of 383, 73.4% of excluded nodules); (b) prior nondiagnostic biopsy results, in which case only the first FNA of a given nodule with nondiagnostic results was included (50 of 383, 13.1%); or (c) insufficient sampling due to early termination of the procedure (three of 383, 0.8%). The remaining 49 of 383 nodules (12.8%) were found in 24 patients. Because some patients had Implication for Patient Care nn Following nondiagnostic thyroid nodule FNA results, US and clinical follow-up may be more appropriate than repeat FNA.

Anderson et al

more than one nodule with initially nondiagnostic results, 49 nodules from 24 people were removed from our analyses to avoid statistical biases associated with violation of independence, resulting in a study cohort of 393 patients with a single nodule with nondiagnostic results, regardless of the presence or absence of other nodules with initially diagnostic results (Figure). The medical records were then reviewed, and the following information was recorded: (a) demographic characteristics, including age at FNA, sex, and ethnicity; (b) location of the nodule within the gland; (c) presence or absence of additional nodules; (d) results of subsequent FNA and US examinations; (e) reports from surgical pathologic examination in the event of partial or complete thyroidectomy; and (f) the date of definitive diagnosis. These materials were analyzed along with the US data detailed below. All patients underwent a US examination of the thyroid by an American Registry for Diagnostic Medical Sonography–certified or American Registry for Diagnostic Medical Sonography–eligible US technologist from our American College of Radiology–accredited department by using high-frequency linear transducers (9–14 MHz) with US units (Logiq 9 and Logiq E9; GE Healthcare, Wauwatosa, Wis) prior to the requested FNA. Images were reviewed by one of 24 attending radiologists specializing in both body imaging and US, including Published online before print 10.1148/radiol.14132134  Content codes: Radiology 2014; 272:777–784 Abbreviations: CI = confidence interval FNA = fine-needle aspiration Author contributions: Guarantors of integrity of entire study, T.J.T.A., M.D.B.; 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; literature research, T.J.T.A., J.J.C., M.D.B.; clinical studies, T.J.T.A., M.K.A., D.J.G., M.D.B.; statistical analysis, T.J.T.A., M.K.A., G.L.B., M.D.B.; and manuscript editing, all authors Conflicts of interest are listed at the end of this article.  n Radiology: Volume 272: Number 3—September 2014

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Flowchart of study nodules.

three authors (M.D.B., M.K.A., and D.J.G., with 7, 11, and 8 years of experience, respectively). The decision to perform FNA was made on the basis of established guidelines, initially from the 2005 Society of Radiologists in Ultrasound consensus conference (8) and subsequently from the Revised 2009 American Thyroid Association Guidelines (10). Alternatively, FNA may have been performed at the request of the referring endocrinologist because of high-risk patient history or anxiety. US-guided FNAs were performed by an attending radiologist or by a radiology resident, fellow, or physician assistant under the direct supervision of an attending radiologist, including three authors (M.D.B., M.K.A., and D.J.G.). Lidocaine 1% (Hospira, Lake Forest, Ill), 3–5 mL, was used for local anesthesia, followed by five passes with 25-gauge needles (Becton, Dickinson, Franklin Lakes, NJ) or 27-gauge needles (Monoject; Kendall Healthcare, Covidien, Mansfield, Mass) using the capillary technique. Samples were collected in 30-mL of cytologic solution (CytoLyt; Cytyc, Londonderry, NH). Each sample was centrifuged for 10 minutes at 600g, the supernatant was decanted, and the pellet was resuspended in 30 mL of the same cytologic solution. Each sample

underwent three such washes before resuspension in a cell preservative solution (PreservCyt; Cytyc). Standard thin sections were then prepared. The slides were stained with hematoxylin and a mixture of staining dyes for cell fixation and permeabilization (Cyto-Stain; Richard Allan Scientific, Kalamazoo, Mich) and reviewed by an attending cytopathologist. Our cytology department uses standard sample adequacy criteria from the Bethesda System for Reporting Thyroid Cytopathology: With these criteria, a sample is classified as having nondiagnostic results (class I) if it has fewer than six groupings of at least 10 thyroid follicular cells each (21,22). US images acquired at the time of biopsy were subsequently reviewed at a picture archiving and communication system workstation (Centricity RA1000; GE Healthcare, Barrington, Ill) by one of three authors (M.D.B., M.K.A., D.J.G). Cine clips were often, but not always, available. In an effort to mitigate any bias, nodules were randomly assigned, and reviewers were blinded to clinical history and subsequent nodule outcome. The following data were recorded for each nodule: (a) maximal diameter in transverse, anteroposterior, and craniocaudal dimensions, from which volume and mean diameter were

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calculated; (b) border contour (regular or irregular); (c) nodule composition (cystic, predominantly cystic [ 50% cystic], spongiform, predominantly solid [ 50% solid], mixed echogenicity solid, hypoechoic solid, isoechoic solid, or hyperechoic solid); and (d) presence or absence of macrocalcifications, microcalcifications, eggshell calcifications, indeterminate calcifications, comet tail artifact, or central vascularity at color Doppler imaging. Indeterminate calcifications were any indeterminate echogenic foci that were larger than the punctate focus typical of psammomatous calcifications associated with papillary thyroid cancer but not large enough to demonstrate the shadowing typical of macrocalcifications.

Statistical Analysis Data were analyzed by using Proc Logistic, Freq, GLM, and TTest in statistical software (SAS 9.3 Software for Windows; SAS Institute, Cary, NC). Significance level was established a priori at P  .05. Because of the low incidence of malignancy in this cohort, typical asymptotic methods may be inappropriate. As a conservative effort, exact univariate logistic regression was used to model the relationship between the odds of malignancy and various nodule 779

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Table 1 Study Sample Demographics Characteristic Overall* White* Black* Asian* Ethnicity unknown* Mean age (y)† Mean age for patients with benign nodules (y)† Mean age for patients with malignancies (y)†

No. of Male Patients

No. of Female Patients

65 (16.5) 59 (90.8) 3 (4.6) 0 (0) 3 (4.6) 60.8 (61, 19–91) 60.5 (60, 19–91) 66.3 (65.5, 57–77)

328 (83.5) 292 (89.0) 19 (5.8) 2 (0.6) 15 (4.6) 54.5 (56, 12–94) 54.4 (56, 12–94) 59.8 (58, 47–71)

Note.—No interaction effect on age was found for malignancy status and sex. * Numbers in parentheses are percentages. Percentages were rounded. †

Numbers in parentheses are medians and ranges.

measurements (23,24); parameter estimate P values were derived from likelihood ratio tests of a single parameter by using exact distributions (25). The Fisher exact test was used to examine the relationship between malignancy and sex. Differences in age according to sex and differences in age according to malignancy status were tested by using the Student independent-samples t test and the Satterthwaite test, respectively, as our data were not skewed and did not violate normality. The interaction of sex and malignancy status was also examined by using the general linear model. As a conservative effort, the Clopper-Pearson method was used for proportion confidence interval (CI) estimation. Tukey-Kramer multiple comparisons were used to test differences in maximum diameter among surgery, FNA, and US. For statistical analyses, nodules were considered benign if (a) a repeat FNA was diagnostic, and results were interpreted as benign (245 of 393, 62.3%); (b) at surgical pathologic examination, a diagnosis of a benign nodule (85 of 393, 21.6%) was determined; or (c) the nodule remained stable at serial US examinations with no evidence of growth or change for a minimum of 1 year following initial FNA (54 of 393, 13.7%).

Results Of the 393 patients in our sample, 83.5% (328 of 393) were female, 780

89.3% (351 of 393) were white, and the median age was 57 years (Table 1). Following nondiagnostic FNA results, 336 nodules (85.5%) underwent repeat FNA. Eighteen of these nodules (5.4% of repeat FNAs) were suspicious for malignancy, prompting surgical removal and pathologic examination, eventually leading to a diagnosis of two malignancies (two of 336, 0.6%), with one papillary and one follicular cancer, and 16 of 336 (4.8%) benign nodules (Figure). The false-positive rate of repeat FNA following nondiagnostic FNA results was 4.9% (16 of 329), with a result that was suspicious for malignancy having a positive predictive value of 11.1% (two of 18). The median time to performance of the FNA with falsepositive results after initial FNA was 54 days, with a mean of 185 days and a range of 8–1011 days. Twelve of 16 (75.0%) FNAs with false-positive results were performed less than 90 days after the initial FNA. Subsequent FNA allowed the diagnosis of 245 of 336 nodules (72.9%) as benign; 167 of 336 (49.7%) were diagnosed on the first repeat FNA, while the rest (78 of 336, 23.2%) were diagnosed as benign at subsequent FNA. Of the remaining 73 nodules, 49 (49 of 336, 14.6%) were surgically excised, yielding four papillary cancers and one follicular cancer, and 24 (24 of 336, 7.1%) were followed up with serial US examinations. Among patients who did not undergo repeat FNA (57 of 393, 14.5%),

Anderson et al

47.4% (27 of 57) underwent surgical excision, which led to the diagnosis of one papillary and one follicular cancer, and in 52.6% (30 of 57), follow-up with serial US examinations was performed. Benignity was established in 54 nodules (54 of 393, 13.7%) through imaging stability (mean follow-up, 3.0 years; median follow-up, 2.5 years; range, 1.0–7.8 years). In total, 92 nodules (92 of 393, 23.4%) were diagnosed at the time of surgery; 85 of 92 (92.4%) of these nodules were benign and seven of 92 (7.6%) of these nodules were malignant (two were follicular and five were papillary cancers). Interestingly, while only seven malignancies were detected in the reference nodules, an additional 25 papillary cancers in 25 patients were discovered incidentally elsewhere in the thyroid gland at the time of surgery (25 of 92, 27.2%, vs seven of 92, 7.6%). Patients undergoing surgery had significantly larger nodules than those who received a diagnosis with FNA (mean maximum diameter, 3.1 vs 2.4 cm; P , .001) or those followed up by using US (3.1 vs 2.1 cm, P , .001). Sex differences were also observed. Male patients represented only 16.5% (65 of 393) of the cohort but accounted for 44.4% (four of nine) of the cancers. As a result, the odds of malignancy were 4.2 times higher for male patients relative to female patients (P = .045). In addition, a significant difference in age was observed. Specifically, the average age of patients with benign nodules was 55.4 years (median, 57 years; range, 12–94 years), while the average age of patients with malignancies was 62.7 years (median, 64 years; range, 47–77 years; P = .0392). It should be noted that, for this cohort, no malignancies were detected in patients younger than 47 years old. Several nodule measurements were found to be significantly associated with the odds of a nodule being malignant (Table 2). For every 1-cm increase in anteroposterior diameter, the odds of malignancy increased by 1.78. Likewise, for every 1-cm increase in mean diameter or minimum diameter, the odds of  n Radiology: Volume 272: Number 3—September 2014

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Table 2 Odds Ratios of Malignancy according to Nodule Measurements Nodule Measurement Transverse diameter Anteroposterior diameter Craniocaudal diameter Minimum diameter Maximum diameter Mean diameter Volume

Odds Ratio*

Parameter Estimate P Value

1.77 (0.995, 3.02) 1.78 (1.08, 2.81) 1.59 (0.94, 2.59) 2.10 (1.11, 3.68) 1.57 (0.95, 2.52) 1.96 (1.09, 3.44) 1.04 (1.00, 1.07)

.052 .027† .081 .024† .075 .027† .051

Note.—Odds ratios are based on a 1-cm increase in diameter or a 1-cm3 increase in volume. * Numbers in parentheses are 95% CIs. †

Denotes a significant difference, with P , .05.

malignancy increased by 1.96 and 2.10, respectively. For every cubic-centimeter increase in volume, the odds of malignancy increased by 1.04, although this relationship only approached significance (P = .051). No malignancies were detected in nodules with spongiform (11 of 393, 2.8%; 95% CI: 1.4%, 5.0%) or cystic (11 of 393, 2.8%; 95% CI: 1.4%, 5.0%) composition, although these combined represented only 5.6% of study nodules (Table 3). Malignancies were otherwise detected in nodules of diverse compositions. All malignancies, except one papillary cancer, had regular borders. No malignancies were detected in nodules with eggshell (nine of 393, 2.3%; 95% CI: 1.1%, 4.3%) or indeterminate (39 of 393, 9.9%; 95% CI: 7.2%, 13.3%) calcifications. Macrocalcifications were noted in one follicular cancer and microcalcifications were noted in one papillary cancer; 44.4% (four of nine) of malignancies were noted to have increased central vascularity, compared with 47.7% (183 of 384) of benign nodules.

Discussion To our knowledge, this is the largest study to date that models patient demographics and nodule US characteristics with final diagnoses following nondiagnostic thyroid FNA results. The 2.3% malignancy rate observed in our cohort is up to sevenfold lower than the malignancy rate for all patients

undergoing initial thyroid FNA (5%– 15%), although the rate is consistent with rates in prior studies of nodules with nondiagnostic results at centers with strict sample adequacy requirements (16,26,27). In addition, in only two of 18 repeat FNAs with nodules that were interpreted as suspicious for malignancy were the nodules actually malignant at surgical pathologic examination, giving a false-positive rate of 4.9% for repeat FNA in our series. The results from our data suggest that an initial appropriately performed biopsy with nondiagnostic results of a single nodule can be a reassuring indication of benignity and that imaging follow-up rather than repeat FNA or surgery should be recommended. It is worth noting that two-thirds of the detected malignancies (six of nine) were papillary cancers, which have an estimated 20-year cancer-specific survival of 97% even without surgical intervention for more than a year after detection (28). Given the indolent clinical course of these cancers, any “delay” in diagnosis caused by follow-up US rather than immediate repeat FNA is probably clinically irrelevant (28). An age younger than 20 years and an age older than 70 years are known risk factors for malignancy (29). Our cohort included only 13 patients younger than 20 years old; however, we detected no cancers in patients younger than 47 years old, and the risk of malignancy increased with advanced age. We propose that patients between 20 and

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45 years old can be treated coservatively following nondiagnostic FNA results (ie, with serial US rather than repeat biopsy). Repeat FNA should be performed if subsequent US examination demonstrates growth. We also noted a difference according to sex. Overall, thyroid cancer is three times more common in women than men (30,31). We have found, however, that following a nondiagnostic result, men have a fourfold higher odds of malignancy than women (P = .045), with an absolute risk of 6.2% (four of 65) for men versus 1.5% (five of 328) for women. Researchers in prior literature state that the initial repeat FNA following a nondiagnostic result will be diagnostic 60% of the time (21,32,33). We found that 247 of 336 (73.5%) of individuals undergoing serial FNA eventually received a diagnosis with FNA cytologic examination; however, only 50% of FNAs were diagnostic on the first repeat FNA (168 of 336, including one papillary carcinoma). In our study, the likelihood of an FNA result that was suspicious for malignancy after a nondiagnostic FNA was low (18 of 336, 5.4%), and in 88.9% (16 of 18) of repeat biopsies that were suspicious for malignancy, the lesions proved to be benign at surgical pathologic examination. Very few malignancies were diagnosed with repeat FNA (two of 336, 0.6%), while slightly more nodules were found to be malignant at the time of surgery (seven of 393, 1.8%). This difference may have been caused by the ability to detect smaller clusters of cancerous cells at surgical pathologic examination, or it may have been caused by selection bias of patients referred for surgery (larger nodules, history of growth or symptoms, a concern about the US appearance). Interestingly, patients who underwent surgical excision of their thyroid gland for a nodule with a nondiagnostic result were far more likely to have a papillary cancer elsewhere in their gland (often microcarcinoma) than to have a cancer in the nodule in question (27.2% vs 7.6%). This is consistent with published literature where papillary cancers incidentally discovered at the time of surgery are very 781

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Table 3 US Features of Nodules with Nondiagnostic Results Feature Composition   Solid, hyperechoic   Solid, isoechoic   Solid, hypoechoic   Solid, mixed   Predominantly solid  Spongiform   Predominantly cystic  Cystic Border  Regular  Irregular Calcifications  Macrocalcifications  Microcalcifications  Eggshell  Indeterminate  None Comet tail artifact  Present  Absent Central vascularity  Present  Absent

Overall No.*

No. of Benign Nodules†

No. of Nodules Stable with US‡

No. of Nodules with Papillary Carcinoma§

No. of Nodules with Follicular Carcinoma ||

9 (2.3) 79 (20.1) 91 (23.2) 33 (8.4) 73 (18.6) 11 (2.8) 86 (21.9) 11 (2.8)

7 (2.1) 71 (21.5) 76 (23.0) 29 (8.8) 62 (18.8) 10 (3.0) 68 (20.6) 7 (2.1)

1 (1.9) 7 (13.0) 12 (22.2) 3 (5.6) 10 (18.5) 1 (1.9) 16 (29.6) 4 (7.4)

1 (16.7) 1 (16.7) 2 (33.3) 0 (0) 1 (16.7) 0 (0) 1 (16.7) 0 (0)

0 (0) 0 (0) 1 (33.3) 1 (33.3) 0 (0) 0 (0) 1 (33.3) 0 (0)

299 (76.1) 94 (23.9)

249 (75.5) 81 (24.5)

42 (77.8) 12 (22.2)

5 (83.3) 1 (16.7)

3 (100) 0 (0)

25 (6.4) 17 (4.3) 9 (2.3) 39 (9.9) 303 (77.1)

20 (6.1) 15 (4.5) 6 (1.8) 33 (10.0) 256 (77.6)

4 (7.4) 1 (1.9) 3 (5.6) 6 (11.1) 40 (74.1)

0 (0) 1 (16.7) 0 (0) 0 (0) 5 (83.3)

1 (33.3) 0 (0) 0 (0) 0 (0) 2 (66.7)

18 (4.6) 375 (95.4)

12 (3.6) 318 (96.4)

6 (11.1) 48 (88.9)

0 (0) 6 (100)

0 (0) 3 (100)

187 (47.6) 206 (52.4)

166 (50.3) 164 (49.7)

17 (31.5) 37 (68.5)

2 (33.3) 4 (66.7)

2 (66.7) 1 (33.3)

Note.—Data in parentheses are percentages. * n =393, total. †

n = 330 (330 of 393, 84.0%).

n = 54 (54 of 393, 13.7%).


n = 6 (six of 393, 1.5%).


n = 3 (three of 393, 0.8%).

common, with malignancy rates among patients undergoing thyroidectomy for “benign” disease ranging from 5% to 50% (34–38). Earlier recommendations advised waiting 3 months after a nondiagnostic result of thyroid FNA before repeating the FNA because of the potential of a false-positive result related to misinterpretation of a reparative postbiopsy effect (39,40). In contrast, the researchers in a recent retrospective study of 226 patients undergoing repeat FNA after a nondiagnostic FNA result found that timing of the repeat FNA did not significantly alter the diagnostic yield of the repeat FNA or yield a significant difference in the cytologic 782

diagnoses between the subgroups: repeat FNA performed less than 3 months or 3 months or longer after initial FNA (41). However, our series showed a 4.9% false-positive rate for repeat FNA with 16 of 18 suspicious for malignancy results at repeat FNA actually being benign results at surgical pathologic examination. In 75% of the false-positive FNA results, FNA was performed less than 3 months after the initial FNA, and perhaps the earlier recommendations of waiting at least 3 months are appropriate. No malignancies were detected in spongiform nodules or purely cystic nodules, and these results are consistent with results in previous reports that

these compositions are at low risk for malignancy (42,43). No malignancies were seen in nodules with eggshell or indeterminate echogenic foci, although nodules with these features make up a combined 12.2% (48 of 393) of the study cohort. In addition to the small number with these features, there can be overlap in the appearance of echogenic foci with calcifications, and, as such, we advise caution in using these criteria as reassuring features. Our results also indicate that some nodule measurements such as anteroposterior, minimum, and mean diameter and volume were found to be significantly associated with increased odds of malignancy. These findings support and  n Radiology: Volume 272: Number 3—September 2014

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expand earlier work proposing the use of FNA outcomes in conjunction with US features to determine the risk of malignancy following FNA (44). By further characterizing the subset of FNAs with a nondiagnostic result and correlating their outcomes with demographic data and additional US parameters, we have substantially strengthened the case that nodules with FNAs with a nondiagnostic result, particularly in the setting of low-risk demographics and benign appearance with US, can be safely followed with serial US examinations. This study was limited by subject attrition due to insufficient follow-up (281 of 776, 36.2% of all biopsies with nondiagnostic results performed during the study period), which could have created sampling bias, although we hypothesize that patients were reassured by their providers, and the lack of follow-up within our system for some cases may reflect, that they had a clinically stable and, thus, benign, nodule. The low incidence of thyroid cancers in our sample (three follicular and six papillary) limits the generalizability of our results; thus, further research with a larger sample size capturing more malignancies needs to be conducted to validate our findings of increased odds of cancer in males following nondiagnostic FNA results. Our cohort also included very few patients younger than 20 years old, so our results cannot be generalized to this age group. In addition, because of the retrospective nature of the study, imaging analysis of nodules could only be made on saved images, which may not have captured all pertinent US features, as cine clips were not always available. Each nodule was scored by only one of the three authors. In an effort to mitigate any bias, nodules were randomly distributed, and readers were blinded to clinical history and subsequent outcomes. Finally, our findings may not be generalizable to all patient populations. Our cohort consisted of patients with a thyroid nodule that was initially not diagnosed with FNA regardless of whether the nodule was solitary or accompanied by other (benign or malignant) thyroid nodules, provided all

other nodules were initially diagnosed with FNA. Although investigators in previous studies indicate that the incidence of malignancy for a single nodule is roughly equivalent between uninodular and multinodular glands when the accompanying nodules are benign, the researchers in these studies do not compare uninodular and multinodular glands when accompanying nodules are malignant (45,46). Although an interesting theoretical question, it is of little clinical value, as patients with a malignant nodule typically will undergo thyroidectomy regardless of the presence of or histologic findings of accompanying nodules. Given the low likelihood of detecting malignancy with repeat FNA following nondiagnostic results with initial FNA, conservative follow-up with serial US examinations instead of repeat biopsy may be appropriate in most patients. Conservative management is particularly appropriate in female patients, patients younger than 45 years old, and patients with entirely cystic or spongiform nodules. Disclosures of Conflicts of Interest: T.J.T.A. No relevant conflicts of interest to disclose. M.K.A. No relevant conflicts of interest to disclose. D.J.G. No relevant conflicts of interest to disclose. G.L.B. No relevant conflicts of interest to disclose. J.J.C. No relevant conflicts of interest to disclose. M.D.B. No relevant conflicts of interest to disclose.

References 1. Vander JB, Gaston EA, Dawber TR. The significance of nontoxic thyroid nodules. Final report of a 15-year study of the incidence of thyroid malignancy. Ann Intern Med 1968;69(3):537–540. 2. Bruneton JN, Balu-Maestro C, Marcy PY, Melia P, Mourou MY. Very high frequency (13 MHz) ultrasonographic examination of the normal neck: detection of normal lymph nodes and thyroid nodules. J Ultrasound Med 1994;13(2):87–90. 3. Ezzat S, Sarti DA, Cain DR, Braunstein GD. Thyroid incidentalomas: prevalence by palpation and ultrasonography. Arch Intern Med 1994;154(16):1838–1840. 4. Guth S, Theune U, Aberle J, Galach A, Bamberger CM. Very high prevalence of thyroid nodules detected by high frequency (13 MHz) ultrasound examination. Eur J Clin Invest 2009;39(8):699–706.

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Management of nodules with initially nondiagnostic results of thyroid fine-needle aspiration: can we avoid repeat biopsy?

To identify demographic and ultrasonographic (US) features associated with malignancy after initially nondiagnostic results of fine-needle aspiration ...
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