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Ultrasonographic features associated with malignancy in cytologically indeterminate thyroid nodules N. Batawil*, T. Alkordy Department of Radiology, Thyroid Nuclear Oncology Clinic, King Abdulaziz University Hospital, P.O. Box 80215, 21589 Jeddah, Saudi Arabia Accepted 15 November 2013 Available online 14 December 2013

Abstract Context: Thyroid nodules with indeterminate cytology usually are treated with surgery, but most are benign. Neck ultrasonography has varied results in predicting malignancy. Objective: To evaluate the predictive value of ultrasonography and the frequency of malignancy in patients who had indeterminate thyroid nodules. Design: Retrospective study. Setting: University hospital. Patients: There were 78 patients who had thyroid nodules that were diagnosed on cytology (fine needle aspiration) as a follicular lesion (atypia of undetermined significant) or follicular neoplasm. Ultrasonography was available in 69 patients (88%). Intervention and main outcome measures: Diagnostic fine needle aspiration (cytology), ultrasonography, and surgical pathology of thyroid nodules. Results: Fine needle aspiration was indeterminate in all patients, with follicular lesions in 60 patients (77%) and follicular neoplasm in 18 patients (23%). Ultrasonography showed micro calcification in 6 patients (9%), irregular border in 15 patients (22%), size  3 cm in 31 patients (45%), and hypoechogenicity in 43 patients (62%). Surgical pathology showed that the nodules were benign in 50 patients (64%) and malignant in 28 patients (36%). Malignancy was significantly associated with male sex (relative risk, 2.3), solid nodule structure (relative risk, 2.6), and irregular border (relative risk, 3.6). Compared with other ultrasonographic characteristics, irregular borders had the highest specificity (93%), positive predictive value (80%), and accuracy (78%) for malignancy. Conclusions: The frequency of malignancy is high in indeterminate thyroid nodules. Based on the limited accuracy or predictive value of ultrasonographic risk factors, surgery is the treatment of choice for indeterminate thyroid nodules. Ó 2013 Elsevier Ltd. All rights reserved. Keywords: Carcinoma; Fine needle aspiration; Cytology; Imaging

Introduction Thyroid nodules are common, and the detection of thyroid nodules has increased because of the availability of neck imaging. Most thyroid nodules are benign, and 95% accuracy, * Corresponding author. Tel.: þ966 2 640 8222; fax: þ966 2 640 8222x18149. E-mail address: [email protected] (N. Batawil). 0748-7983/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2013.11.015

many (15%e30%) fine needle aspirations yield indeterminate cytology such as follicular lesions (atypia of undetermined significant) or follicular neoplasm.2,3 Most lesions with indeterminate cytology are operated and subsequently shown to be benign. Therefore, improved knowledge about risk factors for indeterminate thyroid nodules, such as sex, age, ultrasonographic features, and molecular variables, may decrease the frequency of unnecessary surgery for benign lesions. Ultrasonography is simple, reliable, commonly available, and has high sensitivity (90%) and specificity (85%) for thyroid nodules.4 Ultrasonography may detect pure cystic nodules and has high negative predictive value for

N. Batawil, T. Alkordy / EJSO 40 (2014) 182e186

malignancy. Furthermore, ultrasonography may help guide fine needle aspiration, follow thyroid nodule size, and detect small nodules that are not palpable. Morphologic characteristics of thyroid nodules that may be consistent with malignancy include solid structure, hypoechogenicity, micro calcification, irregular margins,, and regional lymph node metastasis.5e8 A sub-centimeter nodule has low yield of malignancy, FNA is recommended to a nodule of one centimeter or greater.2 However, specific diagnostic criteria do not exist about the diagnostic accuracy of ultrasonography. In a study of 477 patients who had thyroid nodules with indeterminate cytology, malignancy was associated with hypoechogenicity, micro calcification, irregular margins, and tall shape (height > width).9 In another study of 505 thyroid nodules with indeterminate cytology, spot micro calcification was the only reliable ultrasonographic criterion for malignancy.10 Other studies have shown no relation between ultrasonographic features and malignancy in thyroid nodules with indeterminate cytology.5,11,12 Therefore, further information is necessary for reliable use of ultrasonographic results to decrease unnecessary surgery in the diagnosis and treatment of indeterminate thyroid nodules. The purpose of the present study was to evaluate the predictive value of ultrasonography and the frequency of malignancy in patients who had indeterminate thyroid nodules. Materials and methods Patients There were 113 Patients with indeterminate thyroid cytology at King Abdulaziz University Hospital from January 2008 to December 2012. Data for 78 patients with histopathology correlation is available for the study, 35 patients with no corresponding surgical pathology were excluded from the analysis. Medical records were reviewed retrospectively for demographic features, thyroid function tests, radiology reports, ultrasonography results (69 patients; ultrasonography results missing in 9 patients), histopathology diagnosis after fine needle aspiration, surgical pathology reports, and malignant histopathology subtypes. Thyroid ultrasonography and fine needle aspiration Thyroid ultrasonography was performed in real time with a linear-array transducer 7.5e15 MHz (Philips iU22 xMATRIX system and Siemens Sonoline Antares, Germany) that had good resolution for superficial soft tissues such as the thyroid. Ultrasonographic features were determined including nodule size (45 y 45 y Nodule Mixed or cystic Solid Calcification None or coarse Micro calcification Border Regular Irregular Size .05.

most frequent malignancy was papillary or micropapillary carcinoma, and most patients who had a malignant nodule were treated with total thyroidectomy (Table 1). Malignant nodules were more frequent in male than female patients (Table 2). Patients who had benign or malignant nodules had similar mean age (Table 2). Radionuclide thyroid scans had been done in 19 patients (24%), and all scans showed cold thyroid nodules with normal thyroid uptake. All patients had a normal thyroid function test.

The present study showed that solid nodules and irregular borders on ultrasonography may be associated with malignancy in thyroid nodules that have indeterminate cytology on fine needle aspiration (Table 3). However, the risk of malignancy is high (Table 1), and ultrasonographic features of indeterminate thyroid nodes lack sufficient diagnostic reliability (Table 4). Therefore, surgery is recommended for accurate diagnosis of these nodules. The frequency of malignancy in the present study (36%) (Tables 1 and 2) was comparable to the findings of a large prospective multicenter study of 560 indeterminate thyroid nodules (36% malignant) and a review of 11 published studies of fine needle aspiration (14%e48% malignant).13 The most common malignancy in the present patients was papillary or micropapillary thyroid cancer, similar to other studies.11,14 The association of male sex and malignancy in the present patients (Table 3) also is comparable with previous reports.15,16

Table 3 Relation between clinical and ultrasonographic characteristics and risk of developing thyroid cancer.a Characteristic

Sex: male vs femalec Age  45 y vs > 45 y Nodule: solid vs mixed or cysticd Calcification: micro calcification vs none or coarse Border: irregular vs regulare Size  3 cm vs < 3 cm Echogenicity: Hypoechogenic vs isoechogenic or hyperechogenic Solid nodule and irregular borderf a b c d e f



Odds Ratio

95% Confidence interval


Odds Ratio

95% Confidence interval


6.6 1.1 4.4 .9 14 1.2 2.4

1.2e36 .4e3.0 1.5e13 .2e5.5 3.4e58 .6e2.3 .8e7.2

.04 NS .005 NS .0005 NS NS

6.8 1.2 8.6 1.6 8.6 1.1 1.1

1.2e38 .4e3.7 1.7e43 .1e22 1.6e46 .3e4.6 .2e5.6

.03 NS .009 NS .02 NS NS







N ¼ 78 patients; ultrasonography available in 69 patients. NS, not significant; P > .05. Male vs female: relative risk, 2.3 (95% confidence interval, 1.4e4.0). Solid vs mixed or cystic: relative risk, 2.6 (95% confidence interval, 1.3e5.6). Irregular vs regular border: relative risk, 3.6 (95% confidence interval, 2.1e6.3). Combination of 2 ultrasonographic characteristics (univariate only).

N. Batawil, T. Alkordy / EJSO 40 (2014) 182e186


Table 4 Ultrasonographic characteristics compared with surgical biopsy as predictors of thyroid malignancy.a Ultrasonographic characteristic



Positive predictive value

Negative predictive value


Size Nodule echo structure Calcification Border Echogenicity

50 70 8 50 75

58 64 91 93 44

39 52 33 80 42

68 81 65 78 77

55 67 62 78 55


(30e70) (53e89) (3e19) (30e70) (58e92)

(43e72) (50e78) (83e99) (86e100) (30e59)

(22e56) (34e69) (4e71) (60e89) (27e57)

(54e83) (68e93) (53e77) (67e89) (61e93)

(43e67) (56e78) (51e74) (69e88) (43e67)

Data reported as percent (95% confidence interval).

In the present patients, no unique clinical or ultrasonographic characteristics were reliably predictive of malignancy (Tables 3 and 4). Nevertheless, risk factors such as solid nodules and irregular borders, alone or in combination, may help identify high risk patients (Tables 2 and 3). This is consistent with the results of previous studies.11,17,18 Clinical parameters (male patients, age < 25 years, large fixed nodules) have been associated with malignant nodules, but the predictive accuracy is not high enough to enable changes in treatment plans.11,19 In patients who have a cytological diagnosis of atypia and who are treated with thyroidectomy, clinical and ultrasonographic parameters may be combined into a clinical score that may predict the individual risk of malignancy, but malignancy was noted in 16% patients who have a low risk score.10 Other studies have shown no association between ultrasonographic parameters and risk of malignancy in indeterminate thyroid nodules.5,11 Limitations of the present study include the retrospective design and small number of patients, which may affect the confidence intervals and statistical power of the study. Furthermore, genetic markers were not evaluated in the present study; 60%e70% thyroid cancers may have a known genetic mutation, and it may be useful to combine microscopic (fine needle aspiration) and molecular analysis to evaluate thyroid nodules.20 Genetic markers for BRAF, RAS, RET, and VEGF mutations may have high specificity and good predictive accuracy for detecting malignancy in indeterminate thyroid nodules.21e23 In summary, the present study confirmed that the frequency of malignancy is high in indeterminate thyroid nodules (Table 1). Male patients who have follicular lesions with solid structure and irregular borders on ultrasonography are at significantly increased risk for thyroid malignancy compared with female patients who have nonsolid nodules with regular borders. Based on the limited accuracy or predictive value of these risk factors, surgery is the treatment of choice for indeterminate thyroid nodules. Further studies may evaluate other specific markers for improved diagnostic accuracy of malignancy in indeterminate thyroid nodules. Acknowledgments The authors express their gratitude to Dr Iskander Algithmi and Dr Bakr Albakri for their outstanding support.

Funding None. Conflict of interest statement The authors have nothing to disclose.

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Ultrasonographic features associated with malignancy in cytologically indeterminate thyroid nodules.

Thyroid nodules with indeterminate cytology usually are treated with surgery, but most are benign. Neck ultrasonography has varied results in predicti...
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