TIMELY REVIEWS Section Editor: Liron Pantanowitz, M.D.
Ultrasonographic Thyroid Findings Suspicious for Malignancy Nami Azar, M.D.,1* Craig Lance, M.D.,1 Dean Nakamoto, M.D.,1 Claire Michael, M.D.,2 and Jay Wasman, M.D.2
Asymptomatic incidental thyroid nodules (thyroid incidentalomas) are found in up to a third of the adult population. There is notable overlap in the sonographic appearance of benign and malignant thyroid nodules. This paper provides a brief review of the ultrasound findings of thyroid nodules that are suspicious for malignancy with pathologic correlates. We then discuss the standard approach to a fine needle aspiration biopsy of a thyroid nodule at our institution. Finally, we review specific diagnostic challenges in image guided fine needle aspiration biopsies. Diagn. Cytopathol. 2013;41:1107–1114. VC 2013 Wiley Periodicals, Inc.
Key Words: ultrasound
thyroid; biopsy; FNA; papillary; follicular;
Numerous investigations have demonstrated that asymptomatic incidental thyroid nodules are commonly observed in 19–35% of the adult population on ultrasonography with some studies reporting rates up to 67%. Furthermore, thyroid incidentalomas demonstrate increased prevalence in females and the elderly.1–5 Even so, thyroid malignancies are relatively rare, with approximately 60,000 new cases estimated to occur in 2013.6 Malignancies are found in 9.2–12.0% of solitary nodules selected for fine needle aspiration (FNA)7,8 and 6.3% in multinodular goiters selected for FNA7.
1 Department of Radiology, University Hospitals Case Medical Center, Cleveland, Ohio 2 Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio *Correspondence to: Dr. Nami Azar, Department of Radiology, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106. E-mail: [email protected] Received 5 September 2013; Accepted 25 September 2013 DOI: 10.1002/dc.23058 Published online in Wiley Online Library (wileyonlinelibrary.com).
C 2013 WILEY PERIODICALS, INC. V
The management of thyroid incidentalomas remains controversial; however, most sources agree that there is significant overlap in the sonographic appearance of benign and malignant thyroid nodules. Pre-operative image-guided FNA has improved the detection of thyroid cancer leading to decreased frequency of thyroid surgery while increasing cancer detection rates at surgery.9–12 This brief review discusses ultrasonographic findings of thyroid nodules which are concerning for malignancy and provides discussion of the methods of fine needle aspiration performed at our academic institution. Corresponding radiographic images with pathologic correlates are provided.
Imaging Findings Suggestive of Malignancy on Ultrasound Calcifications Thyroid calcifications, while not sensitive, are a relatively specific ultrasonographic indicator of thyroid carcinoma. Specifically, microcalcifications (representing fine stippled psammomatous calcifications) have been found to be associated with papillary thyroid carcinoma (Figs. 1– 5).13,14 Additionally, intranodular calcifications have been associated with increased risk of malignancy on FNA while annular peripheral calcifications, crescentic peripheral calcifications, and isolated calcified spots without surrounding nodules have not demonstrated similar increased risk.14
Vascularity Nodule vascularity is readily assessed with color Doppler ultrasonography. Multiple series have demonstrated that 42–74% of malignancies exhibit hypervascularity and a predominantly central blood flow (Fig. 6). However, there Diagnostic Cytopathology, Vol 41, No 12
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Fig. 1. Ultrasound image of the right thyroid lobe showing microcalcifications (white arrows) within a large hypoechoic nodule. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Fig. 4. Fine needle aspiration biopsy of this left neck lymph node contains rare follicular groups with marked nuclear crowding, nuclear enlargement, and irregular nuclear membranes suspicious for papillary thyroid carcinoma (Diff Quick, 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 2. Ultrasound image of a left thyroid nodule shows punctuate microcalcifications in the nodule. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 5. Surgical excision of the suspicious lymph node shows a papillary neoplasm with nuclear features diagnostic of papillary thyroid carcinoma (H&E, 2003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
is still a relatively high rate of malignant lesions ranging up to 14–20% which are not hypervascular and demonstrate predominantly peripheral blood flow suggesting that the absence of hypervascular flow cannot reliably exclude the diagnosis of thyroid malignancy.7,15,16
Margin
Fig. 3. Further evaluation shows microcalcifications (red arrow) within a lymph node (white arrows) along the left carotid sheath. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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The presence of irregular margins and absence of hypoechoic halo around the nodule is suggestive of malignancy. Ultrasonographic visualization of local invasion is insensitive (occurring only in 12% of examined malignancies in one series) but highly specific indicator of thyroid malignancy17 (Figs. 7–9).
Diagnostic Cytopathology DOI 10.1002/dc
ULTRASONOGRAPHIC THYROID FINDINGS
Fig. 6. Ultrasound image with color Doppler of papillary thyroid carcinoma demonstrates intranodular vascular flow (white arrow). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 8. Fine needle aspiration from this case shows scattered crowded sheets and clusters of follicular cells suspicious for a follicular neoplasm; the chromatin is powdery and rare nuclear grooves are present (arrow; Papanicolaou stain, 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 9. On resection, this follicular-patterned lesion shows nuclear features diagnostic of papillary thyroid carcinoma (H&E stain, 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Fig. 7. Ultrasound image of right-sided papillary thyroid carcinoma (white arrows) with extension beyond the thyroid capsule into the right common carotid artery (red arrow). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Elastography Ultrasound compression elastography (UE) is a method of measuring tissue strain and elastic modulus using ultrasound imaging while compressive force is applied to the tissue. The alternative method is shear wave elastography which provides similar information independent from operator manual compression. Data reproducibility is more reliable using this method. Results can be inter-
preted using a color graded scale or using a quantification package [a numeric scale where a large strain ratio represents stiffer (less elastic) tissue (Figs. 10–12)]. In our experience with 98 patients, quantitative elastography strain ratios were significantly higher in malignant nodules when compared to benign lesions. In our series, elastography values of less than 1.0 (soft nodules) had a high negative predicative value of 98%.
General Morphology Nodule size is a non-specific finding; however, larger nodules demonstrate increased rates of malignancy on Diagnostic Cytopathology, Vol 41, No 12
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biopsy. The relationship between size and malignancy rates is not linear and the approximate threshold for increased malignancy is 2 cm, beyond which cancer rates do not increase.18 The natural history of both malignant and benign nodules is growth over time.19–21 Even so, Society of Radiologists in Ultrasound consensus opinion is that substantial growth is indicative of an elevated risk of malignancy and warrants ultrasound guided FNA. This consensus
opinion did not characterize how to define substantial growth or provide guidelines for monitoring.22 The number of nodules is similarly non-specific. There is conflicting evidence regarding whether an increasing number of nodules is associated with a lower risk of thyroid carcinoma. For example, a recent article found that in patients referred for thyroidectomy for a diagnosis of follicular neoplasm, H€urthe-cell neoplasm, or indeterminate tumor (excluding suspected papillary thyroid cancer), the presence of additional nodules on screening ultrasound was associated with lower risk of malignancy on final post-operative surgical pathology than on patients with a solitary nodule;23 however, the predominance of the evidence suggests that the overall rate of cancer remains similar despite the number of nodules visualized.7,8,24 Suspicious ultrasonographic findings are summarized in Table I.
Approach to a Thyroid Biopsy
Fig. 10. Color Doppler image demonstrates a uniform nodule with peripheral vascularity. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
In our institution, ultrasound guided FNA of a thyroid nodule is performed on nodules expressing suspicious sonographic appearance as detailed above. A solitary nodule larger than 1 cm is usually targeted for FNA. This is mainly performed when microcalcifications, increased stiffness on elastography, or central vascular flow are detected on ultrasound. In case of multinodular goiter, the
Fig. 11. Elastography on this nodule prior to the biopsy shows a dramatic increase in relative nodule stiffness when compared to the surrounding tissue (ratio of 123). This finding is suggestive of malignancy. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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Diagnostic Cytopathology DOI 10.1002/dc
ULTRASONOGRAPHIC THYROID FINDINGS
Fig. 12. This case was diagnosed as suspicious for follicular neoplasm due to the presence of microfollicles (arrows) and the absence of colloid (Papanicolaou stain, 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 14. This case was diagnosed as benign follicular nodule due to the presence of abundant pale blue watery colloid and rare scattered loosely cohesive clusters of uniform follicular cells (arrow) (Diff Quick stain, 1003) [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Table I. Summary of Suspicious Ultrasound Findings Calcifications: either microcalcifications or intranodular calcifications Hypervascularity Irregular or ill-defined margins Evidence of local invasion Increased nodule stiffness (as measured on elastography) Large nodule size: increased risk up to 2 cm in size Substantial growth over time
Fig. 15. Ultrasound images demonstrate a 2 cm thyroid nodule with cystic changes (white arrow), central flow, and microcalcifications (red arrow). The sonographic findings are suspicious for malignancy. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 13. Transverse ultrasound image shows small (1 cm) nodule in the left lobe with cystic changes centrally. No evidence of central fllow is noted. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
largest nodule on each side is targeted for biopsy. When multiple nodules are present, we also utilize additional criteria such as central vascular flow, presence of cystic changes, and elastography to further target suspicious thyroid nodules for biopsy. Using a high resolution ultrasound transducer (8–15 MHz), screening examination of the thyroid is performed.
Nodule size, margins, local invasion, and microcalcifications are evaluated. Color ultrasound is utilized to evaluate nodule vascularity and any dominant vessels crossing the needle projection. The presence of cervical adenopathy or compression of surrounding structures is also assessed. Subsequently, the region of interest is prepped and draped in the usual sterile manner and local anesthesia is achieved with 1% Lidocaine. In our practice, conscious sedation with Fentanyl and Versed has been used consistently with great patient satisfaction. Diagnostic Cytopathology, Vol 41, No 12
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Fig. 16. This case shows a crowded syncytial sheet of follicular epithelial cells. Note the nuclear grooves identifiable in some cells (arrows). The findings were diagnosed as follicular neoplasm with features suggestive of papillary thyroid carcinoma (Papanicolaou stain, 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 18. Longitudinal access of a thyroid nodule (green arrows). The entire course of the needle (red arrow) is visualized. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 19. Transverse access of a thyroid nodule (green arrow). The tip of the needle (red arrow) is identified within the nodule, but the course of the needle is not visualized. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Fig. 17. On resection, this follicular-patterned lesion shows nuclear features diagnostic of papillary thyroid carcinoma (H&E stain, 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
With ultrasound guidance, thyroid lesions can be biopsied using a transverse or longitudinal approach depending on operator training and comfort level. From an academic point of view, both methods should be used to guarantee accurate access to the nodule; however, this is rarely done in clinical practice. The longitudinal approach enables full length visualization of the needle, but the precise location of the tip within the nodule may be challenging to visualize for inexperienced operators. On the other hand, a transverse approach enables accurate visualization of the needle tip within the nodule; however the course and projection of the needle is not visualized (Figs. 18 and 19). 1112
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Under direct sonographic visualization, a 25 gauge spinal needle is advanced into the nodule of interest and cells are harvested utilizing the capillary method with focus maintained on harvesting multiple areas of the nodule to maximize sample cellularity and minimize sampling error. Following each pass, a drop of the sample is deposited on a slide and gently smeared with another slide. One slide is air dried and stained with Diff-Quik and the other is fixed in alcohol and stained with Papanicolaou stain. The remaining sample is rinsed in cytoLytTM and used for either a ThinPrep or cell block. The air dried smear is reviewed and on-site evaluation is performed by an attending pathologist for determination of adequacy of the sample. Three passes are routinely performed and additional passes may be performed as requested by Pathology.
Diagnostic Cytopathology DOI 10.1002/dc
ULTRASONOGRAPHIC THYROID FINDINGS
Note that aspiration of the nodule is not performed on a routine basis as there is some data to suggest that the samples obtained by the capillary method may be qualitatively easier to interpret.25–27 More recent comparative studies specific to the thyroid have demonstrated that the diagnostic quality of the specimens obtained through the capillary method are not significantly different from those obtained by aspiration.28,29 If there is a paucity of cells obtained on the first three passes, a 22 gauge spinal needle may be utilized to perform an additional two passes utilizing the capillary or aspiration techniques depending on operator preference. In rare occasions, core biopsy of the nodule is performed when adequate cells cannot be obtained or when the pathologist feel that core biopsy might have added value. After completing the biopsy, the thyroid is evaluated with gray scale and color Doppler images to assess for any hemorrhage or hematoma. Normal flow in the carotid artery is documented when an adjacent nodule is biopsied because of the theoretical risk of dissection.
Advanced Techniques Several advantages may be obtained by aggressive use of color Doppler imaging during an ultrasound guided biopsy. In addition to evaluation of the target nodule for hypervascularity as described above, ultrasound Doppler twinkle artifact may be utilized to confidently localize a needle for an inexperienced operator. In the setting of hypervascular nodules, another major benefit of performing thyroid FNA with color Doppler is maximizing sample cellularity by selecting solid nodule components as target areas for the biopsy needle. Ultrasonographic contrast agents are widely available and used in both Europe and Asia; however, regulatory issues continue to limit use in the United States. These contrast agents are gas-filled microbubbles that are injected into the systemic circulation. Microbubbles demonstrate a high degree of echogenicity and can demonstrate microcirculation substantially beyond the resolution of both power and color Doppler imaging. Preliminary investigation has been performed which suggests that contrast enhancement may provide a role in characterization of indeterminate nodules.30,31 Recent prospective evaluation indicates that contrast enhancement can improve specificity, although sensitivity remains similar to unenhanced sonographic evaluation.32
Diagnostic Dilemmas Patients are commonly referred with multiple nodules or advanced multi-nodular goiter. It can be challenging to minimize sampling error by selecting the nodule or nodules which the highest potential for containing atypical cells for biopsy. In addition to nodule selection by evalu-
ating the characteristics outlined in Table I, we would like to re-emphasize the potential for quantitative elastography to provide an objective method of differentiating abnormal tissue. These differences may be entirely occult on grey-scale and color Doppler utrasonography. Another common challenge for both the referring physician and the interventionalist is a non-diagnostic biopsy. Multiple large series at several institutions have documented non-diagnostic FNA rates ranging from 5% to 20%. On follow up surgery or repeat biopsy, occurrence of malignancy in patients with a non-diagnostic FNAB has been demonstrated to range from 5% to 8.5%.33–36 Certainly, evaluation of the FNA samples at the time of the biopsy by pathology staff is one technique to minimize rates of non-diagnostic aspiration biopsies. Even so, given the non-trivial rates of malignancy following nondiagnostic biopsies, either repeat FNA35,36 or core needle biopsy of the lesion34,37,38 has been recommended following an inadequate or non-diagnostic biopsy. Core needle biopsy has been demonstrated to be a more sensitive, albeit more invasive technique.37 Given that the relative risk of a core needle biopsy is significantly less than a thyroidectomy and that a large majority of patients do not ultimately have a malignancy, the operator should not hesitate to consider a core needle biopsy if the alternative is surgical resection.
Acknowledgment NA has Research agreement with Toshiba and DN has Research agreement with Toshiba and Research support from Galil Medical.
References 1. Ezzat S, Sarti DA, Cain DR, Braunstein GD. Thyroid incidentalomas. Prevalence by palpation and ultrasonography. Arch Intern Med 1994 ;154:1838–1840. 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 Off J Am Inst Ultrasound Med 1994;13:87– 90. 3. Woestyn J, Afschrift M, Schelstraete K, Vermeulen A. Demonstration of nodules in the normal thyroid by echography. Br J Radiol 1985;58:1179–1182. 4. Brander A, Viikinkoski P, Nickels J, Kivisaari L. Thyroid gland: US screening in a random adult population. Radiology 1991;181: 683–687. 5. Dean DS, Gharib H. Epidemiology of thyroid nodules. Best Pract Res Clin Endocrinol Metab 2008;22:901–911. 6. Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin 2013;63:11–30. 7. Papini E, Guglielmi R, Bianchini A, et al. Risk of malignancy in nonpalpable thyroid nodules: Predictive value of ultrasound and color-Doppler features. J Clin Endocrinol Metab 2002;87:1941– 1946. 8. Nam-Goong IS, Kim HY, Gong G, et al. Ultrasonography-guided fine-needle aspiration of thyroid incidentaloma: Correlation with pathological findings. Clin Endocrinol (Oxf) 2004;60:21–28. Diagnostic Cytopathology, Vol 41, No 12
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AZAR ET AL. 9. Mittendorf EA, Tamarkin SW, McHenry CR. The results of ultrasound-guided fine-needle aspiration biopsy for evaluation of nodular thyroid disease. Surgery 2002;132:648–653; discussion 653–654. 10. Gharib H, Goellner JR. Fine-needle aspiration biopsy of the thyroid: An appraisal. Ann Intern Med 1993;118:282–289. 11. Gharib H. Fine-needle aspiration biopsy of thyroid nodules: Advantages, limitations, and effect. Mayo Clin Proc Mayo Clin 1994;69: 44–49. 12. Danese D, Sciacchitano S, Farsetti A, Andreoli M, Pontecorvi A. Diagnostic accuracy of conventional versus sonography-guided fineneedle aspiration biopsy of thyroid nodules. Thyroid Off J Am Thyroid Assoc 1998;8:15–21. 13. Wang N, Xu Y, Ge C, Guo R, Guo K. Association of sonographically detected calcification with thyroid carcinoma. Head Neck 2006;28:1077–1083. 14. Kim BK, Choi YS, Kwon HJ, et al. Relationship between patterns of calcification in thyroid nodules and histopathologic findings. Endocr J 2013;60:155–160. 15. Frates MC, Benson CB, Doubilet PM, Cibas ES, Marqusee E. Can color Doppler sonography aid in the prediction of malignancy of thyroid nodules? J Ultrasound Med Off J Am Inst Ultrasound Med 2003;22:127–131; quiz 132–134. 16. De Nicola H, Szejnfeld J, Logullo AF, Wolosker AMB, Souza LRMF, Chiferi V Jr. Flow pattern and vascular resistive index as predictors of malignancy risk in thyroid follicular neoplasms. J Ultrasound Med Off J Am Inst Ultrasound Med 2005;24:897–904. 17. Koike E, Noguchi S, Yamashita H, et al. Ultrasonographic characteristics of thyroid nodules: prediction of malignancy. Arch Surg Chic Ill 1960 2001;136:334–337. 18. Kamran SC, Marqusee E, Kim MI, et al. Thyroid nodule size and prediction of cancer. J Clin Endocrinol Metab 2013;98:564–570. 19. Alexander EK, Hurwitz S, Heering JP, et al. Natural history of benign solid and cystic thyroid nodules. Ann Intern Med 2003;138: 315–318. 20. Quadbeck B, Pruellage J, Roggenbuck U, et al. Long-term followup of thyroid nodule growth. Exp Clin Endocrinol Diabetes Off J Ger Soc Endocrinol Ger Diabetes Assoc 2002;110:348–354. 21. Grant CS, Hay ID, Gough IR, McCarthy PM, Goellner JR. Longterm follow-up of patients with benign thyroid fine-needle aspiration cytologic diagnoses. Surgery 1989;106:980–985; discussion 985–986. 22. Frates MC, Benson CB, Charboneau JW, et al. Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement. Radiology 2005;237:794–800. 23. Sippel RS, Elaraj DM, Khanafshar E, Kebebew E, Duh Q-Y, Clark OH. Does the presence of additional thyroid nodules on ultrasound alter the risk of malignancy in patients with a follicular neoplasm of the thyroid? Surgery 2007;142:851–857; discussion 857.e1–2. 24. Heged€us L, Bonnema SJ, Bennedbaek FN. Management of simple nodular goiter: Current status and future perspectives. Endocr Rev 2003;24:102–132.
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25. Mair S, Dunbar F, Becker PJ, Du Plessis W. Fine needle cytology: Is aspiration suction necessary? A study of 100 masses in various sites. Acta Cytol 1989;33:809–813. 26. Santos JE, Leiman G. Nonaspiration fine needle cytology. Application of a new technique to nodular thyroid disease. Acta Cytol 1988;32:353–356. 27. Fagelman D, Chess Q. Nonaspiration fine-needle cytology of the liver: A new technique for obtaining diagnostic samples. AJR Am J Roentgenol 1990;155:1217–1219. 28. De Carvalho GA, Paz-Filho G, Cavalcanti TC, Graf H. Adequacy and diagnostic accuracy of aspiration vs. capillary fine needle thyroid biopsies. Endocr Pathol 2009;20:204–208. 29. Tublin ME, Martin JA, Rollin LJ, Pealer K, Kurs-Lasky M, Ohori NP. Ultrasound-guided fine-needle aspiration versus fine-needle capillary sampling biopsy of thyroid nodules: Does technique matter? J Ultrasound Med Off J Am Inst Ultrasound Med 2007;26: 1697–1701. 30. Molinari F, Mantovani A, Deandrea M, Limone P, Garberoglio R, Suri JS. Characterization of single thyroid nodules by contrastenhanced 3-D ultrasound. Ultrasound Med Biol 2010;36:1616– 1625. 31. Carraro R, Molinari F, Deandrea M, Garberoglio R, Suri JS. Characterization of thyroid nodules by 3-D contrast-enhanced ultrasound imaging. Conf Proc IEEE Eng Med Biol Soc 2008;2008:2229– 2232. 32. Cantisani V, Consorti F, Guerrisi A, et al. Prospective comparative evaluation of quantitative-elastosonography (Q-elastography) and contrast-enhanced ultrasound for the evaluation of thyroid nodules: Preliminary experience. Eur J Radiol 2013;82:1892–1898. 33. Chow LS, Gharib H, Goellner JR, van Heerden JA. Nondiagnostic thyroid fine-needle aspiration cytology: Management dilemmas. Thyroid Off J Am Thyroid Assoc 2001;11:1147–1151. 34. Samir AE, Vij A, Seale MK, et al. Ultrasound-guided percutaneous thyroid nodule core biopsy: Clinical utility in patients with prior nondiagnostic fine-needle aspirate. Thyroid Off J Am Thyroid Assoc 2012;22:461–467. 35. Alexander EK, Heering JP, Benson CB, et al. Assessment of nondiagnostic ultrasound-guided fine needle aspirations of thyroid nodules. J Clin Endocrinol Metab 2002;87:4924–4927. 36. Orija IB, Pi~ neyro M, Biscotti C, Reddy SSK, Hamrahian AH. Value of repeating a nondiagnostic thyroid fine-needle aspiration biopsy. Endocr Pr Off J Am Coll Endocrinol Am Assoc Clin Endocrinol 2007;13:735–742. 37. Yeon JS, Baek JH, Lim HK, et al. Thyroid nodules with initially nondiagnostic cytologic results: The role of core-needle biopsy. Radiology 2013;268:274–280. 38. Na DG, Kim J, Sung JY, et al. Core-needle biopsy is more useful than repeat fine-needle aspiration in thyroid nodules read as nondiagnostic or atypia of undetermined significance by the Bethesda system for reporting thyroid cytopathology. Thyroid Off J Am Thyroid Assoc 2012;22:468–475.
Ultrasonographic Thyroid Findings Suspicious for Malignancy Nami Azar, M.D.,1* Craig Lance, M.D.,1 Dean Nakamoto, M.D.,1 Claire Michael, M.D.,2 and Jay Wasman, M.D.2
Asymptomatic incidental thyroid nodules (thyroid incidentalomas) are found in up to a third of the adult population. There is notable overlap in the sonographic appearance of benign and malignant thyroid nodules. This paper provides a brief review of the ultrasound findings of thyroid nodules that are suspicious for malignancy with pathologic correlates. We then discuss the standard approach to a fine needle aspiration biopsy of a thyroid nodule at our institution. Finally, we review specific diagnostic challenges in image guided fine needle aspiration biopsies. Diagn. Cytopathol. 2013;41:1107–1114. VC 2013 Wiley Periodicals, Inc.
Key Words: ultrasound
thyroid; biopsy; FNA; papillary; follicular;
Numerous investigations have demonstrated that asymptomatic incidental thyroid nodules are commonly observed in 19–35% of the adult population on ultrasonography with some studies reporting rates up to 67%. Furthermore, thyroid incidentalomas demonstrate increased prevalence in females and the elderly.1–5 Even so, thyroid malignancies are relatively rare, with approximately 60,000 new cases estimated to occur in 2013.6 Malignancies are found in 9.2–12.0% of solitary nodules selected for fine needle aspiration (FNA)7,8 and 6.3% in multinodular goiters selected for FNA7.
1 Department of Radiology, University Hospitals Case Medical Center, Cleveland, Ohio 2 Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio *Correspondence to: Dr. Nami Azar, Department of Radiology, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106. E-mail: [email protected] Received 5 September 2013; Accepted 25 September 2013 DOI: 10.1002/dc.23058 Published online in Wiley Online Library (wileyonlinelibrary.com).
C 2013 WILEY PERIODICALS, INC. V
The management of thyroid incidentalomas remains controversial; however, most sources agree that there is significant overlap in the sonographic appearance of benign and malignant thyroid nodules. Pre-operative image-guided FNA has improved the detection of thyroid cancer leading to decreased frequency of thyroid surgery while increasing cancer detection rates at surgery.9–12 This brief review discusses ultrasonographic findings of thyroid nodules which are concerning for malignancy and provides discussion of the methods of fine needle aspiration performed at our academic institution. Corresponding radiographic images with pathologic correlates are provided.
Imaging Findings Suggestive of Malignancy on Ultrasound Calcifications Thyroid calcifications, while not sensitive, are a relatively specific ultrasonographic indicator of thyroid carcinoma. Specifically, microcalcifications (representing fine stippled psammomatous calcifications) have been found to be associated with papillary thyroid carcinoma (Figs. 1– 5).13,14 Additionally, intranodular calcifications have been associated with increased risk of malignancy on FNA while annular peripheral calcifications, crescentic peripheral calcifications, and isolated calcified spots without surrounding nodules have not demonstrated similar increased risk.14
Vascularity Nodule vascularity is readily assessed with color Doppler ultrasonography. Multiple series have demonstrated that 42–74% of malignancies exhibit hypervascularity and a predominantly central blood flow (Fig. 6). However, there Diagnostic Cytopathology, Vol 41, No 12
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Fig. 1. Ultrasound image of the right thyroid lobe showing microcalcifications (white arrows) within a large hypoechoic nodule. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Fig. 4. Fine needle aspiration biopsy of this left neck lymph node contains rare follicular groups with marked nuclear crowding, nuclear enlargement, and irregular nuclear membranes suspicious for papillary thyroid carcinoma (Diff Quick, 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 2. Ultrasound image of a left thyroid nodule shows punctuate microcalcifications in the nodule. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 5. Surgical excision of the suspicious lymph node shows a papillary neoplasm with nuclear features diagnostic of papillary thyroid carcinoma (H&E, 2003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
is still a relatively high rate of malignant lesions ranging up to 14–20% which are not hypervascular and demonstrate predominantly peripheral blood flow suggesting that the absence of hypervascular flow cannot reliably exclude the diagnosis of thyroid malignancy.7,15,16
Margin
Fig. 3. Further evaluation shows microcalcifications (red arrow) within a lymph node (white arrows) along the left carotid sheath. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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The presence of irregular margins and absence of hypoechoic halo around the nodule is suggestive of malignancy. Ultrasonographic visualization of local invasion is insensitive (occurring only in 12% of examined malignancies in one series) but highly specific indicator of thyroid malignancy17 (Figs. 7–9).
Diagnostic Cytopathology DOI 10.1002/dc
ULTRASONOGRAPHIC THYROID FINDINGS
Fig. 6. Ultrasound image with color Doppler of papillary thyroid carcinoma demonstrates intranodular vascular flow (white arrow). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 8. Fine needle aspiration from this case shows scattered crowded sheets and clusters of follicular cells suspicious for a follicular neoplasm; the chromatin is powdery and rare nuclear grooves are present (arrow; Papanicolaou stain, 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 9. On resection, this follicular-patterned lesion shows nuclear features diagnostic of papillary thyroid carcinoma (H&E stain, 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Fig. 7. Ultrasound image of right-sided papillary thyroid carcinoma (white arrows) with extension beyond the thyroid capsule into the right common carotid artery (red arrow). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Elastography Ultrasound compression elastography (UE) is a method of measuring tissue strain and elastic modulus using ultrasound imaging while compressive force is applied to the tissue. The alternative method is shear wave elastography which provides similar information independent from operator manual compression. Data reproducibility is more reliable using this method. Results can be inter-
preted using a color graded scale or using a quantification package [a numeric scale where a large strain ratio represents stiffer (less elastic) tissue (Figs. 10–12)]. In our experience with 98 patients, quantitative elastography strain ratios were significantly higher in malignant nodules when compared to benign lesions. In our series, elastography values of less than 1.0 (soft nodules) had a high negative predicative value of 98%.
General Morphology Nodule size is a non-specific finding; however, larger nodules demonstrate increased rates of malignancy on Diagnostic Cytopathology, Vol 41, No 12
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biopsy. The relationship between size and malignancy rates is not linear and the approximate threshold for increased malignancy is 2 cm, beyond which cancer rates do not increase.18 The natural history of both malignant and benign nodules is growth over time.19–21 Even so, Society of Radiologists in Ultrasound consensus opinion is that substantial growth is indicative of an elevated risk of malignancy and warrants ultrasound guided FNA. This consensus
opinion did not characterize how to define substantial growth or provide guidelines for monitoring.22 The number of nodules is similarly non-specific. There is conflicting evidence regarding whether an increasing number of nodules is associated with a lower risk of thyroid carcinoma. For example, a recent article found that in patients referred for thyroidectomy for a diagnosis of follicular neoplasm, H€urthe-cell neoplasm, or indeterminate tumor (excluding suspected papillary thyroid cancer), the presence of additional nodules on screening ultrasound was associated with lower risk of malignancy on final post-operative surgical pathology than on patients with a solitary nodule;23 however, the predominance of the evidence suggests that the overall rate of cancer remains similar despite the number of nodules visualized.7,8,24 Suspicious ultrasonographic findings are summarized in Table I.
Approach to a Thyroid Biopsy
Fig. 10. Color Doppler image demonstrates a uniform nodule with peripheral vascularity. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
In our institution, ultrasound guided FNA of a thyroid nodule is performed on nodules expressing suspicious sonographic appearance as detailed above. A solitary nodule larger than 1 cm is usually targeted for FNA. This is mainly performed when microcalcifications, increased stiffness on elastography, or central vascular flow are detected on ultrasound. In case of multinodular goiter, the
Fig. 11. Elastography on this nodule prior to the biopsy shows a dramatic increase in relative nodule stiffness when compared to the surrounding tissue (ratio of 123). This finding is suggestive of malignancy. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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Fig. 12. This case was diagnosed as suspicious for follicular neoplasm due to the presence of microfollicles (arrows) and the absence of colloid (Papanicolaou stain, 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 14. This case was diagnosed as benign follicular nodule due to the presence of abundant pale blue watery colloid and rare scattered loosely cohesive clusters of uniform follicular cells (arrow) (Diff Quick stain, 1003) [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Table I. Summary of Suspicious Ultrasound Findings Calcifications: either microcalcifications or intranodular calcifications Hypervascularity Irregular or ill-defined margins Evidence of local invasion Increased nodule stiffness (as measured on elastography) Large nodule size: increased risk up to 2 cm in size Substantial growth over time
Fig. 15. Ultrasound images demonstrate a 2 cm thyroid nodule with cystic changes (white arrow), central flow, and microcalcifications (red arrow). The sonographic findings are suspicious for malignancy. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 13. Transverse ultrasound image shows small (1 cm) nodule in the left lobe with cystic changes centrally. No evidence of central fllow is noted. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
largest nodule on each side is targeted for biopsy. When multiple nodules are present, we also utilize additional criteria such as central vascular flow, presence of cystic changes, and elastography to further target suspicious thyroid nodules for biopsy. Using a high resolution ultrasound transducer (8–15 MHz), screening examination of the thyroid is performed.
Nodule size, margins, local invasion, and microcalcifications are evaluated. Color ultrasound is utilized to evaluate nodule vascularity and any dominant vessels crossing the needle projection. The presence of cervical adenopathy or compression of surrounding structures is also assessed. Subsequently, the region of interest is prepped and draped in the usual sterile manner and local anesthesia is achieved with 1% Lidocaine. In our practice, conscious sedation with Fentanyl and Versed has been used consistently with great patient satisfaction. Diagnostic Cytopathology, Vol 41, No 12
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Fig. 16. This case shows a crowded syncytial sheet of follicular epithelial cells. Note the nuclear grooves identifiable in some cells (arrows). The findings were diagnosed as follicular neoplasm with features suggestive of papillary thyroid carcinoma (Papanicolaou stain, 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 18. Longitudinal access of a thyroid nodule (green arrows). The entire course of the needle (red arrow) is visualized. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 19. Transverse access of a thyroid nodule (green arrow). The tip of the needle (red arrow) is identified within the nodule, but the course of the needle is not visualized. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Fig. 17. On resection, this follicular-patterned lesion shows nuclear features diagnostic of papillary thyroid carcinoma (H&E stain, 4003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
With ultrasound guidance, thyroid lesions can be biopsied using a transverse or longitudinal approach depending on operator training and comfort level. From an academic point of view, both methods should be used to guarantee accurate access to the nodule; however, this is rarely done in clinical practice. The longitudinal approach enables full length visualization of the needle, but the precise location of the tip within the nodule may be challenging to visualize for inexperienced operators. On the other hand, a transverse approach enables accurate visualization of the needle tip within the nodule; however the course and projection of the needle is not visualized (Figs. 18 and 19). 1112
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Under direct sonographic visualization, a 25 gauge spinal needle is advanced into the nodule of interest and cells are harvested utilizing the capillary method with focus maintained on harvesting multiple areas of the nodule to maximize sample cellularity and minimize sampling error. Following each pass, a drop of the sample is deposited on a slide and gently smeared with another slide. One slide is air dried and stained with Diff-Quik and the other is fixed in alcohol and stained with Papanicolaou stain. The remaining sample is rinsed in cytoLytTM and used for either a ThinPrep or cell block. The air dried smear is reviewed and on-site evaluation is performed by an attending pathologist for determination of adequacy of the sample. Three passes are routinely performed and additional passes may be performed as requested by Pathology.
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Note that aspiration of the nodule is not performed on a routine basis as there is some data to suggest that the samples obtained by the capillary method may be qualitatively easier to interpret.25–27 More recent comparative studies specific to the thyroid have demonstrated that the diagnostic quality of the specimens obtained through the capillary method are not significantly different from those obtained by aspiration.28,29 If there is a paucity of cells obtained on the first three passes, a 22 gauge spinal needle may be utilized to perform an additional two passes utilizing the capillary or aspiration techniques depending on operator preference. In rare occasions, core biopsy of the nodule is performed when adequate cells cannot be obtained or when the pathologist feel that core biopsy might have added value. After completing the biopsy, the thyroid is evaluated with gray scale and color Doppler images to assess for any hemorrhage or hematoma. Normal flow in the carotid artery is documented when an adjacent nodule is biopsied because of the theoretical risk of dissection.
Advanced Techniques Several advantages may be obtained by aggressive use of color Doppler imaging during an ultrasound guided biopsy. In addition to evaluation of the target nodule for hypervascularity as described above, ultrasound Doppler twinkle artifact may be utilized to confidently localize a needle for an inexperienced operator. In the setting of hypervascular nodules, another major benefit of performing thyroid FNA with color Doppler is maximizing sample cellularity by selecting solid nodule components as target areas for the biopsy needle. Ultrasonographic contrast agents are widely available and used in both Europe and Asia; however, regulatory issues continue to limit use in the United States. These contrast agents are gas-filled microbubbles that are injected into the systemic circulation. Microbubbles demonstrate a high degree of echogenicity and can demonstrate microcirculation substantially beyond the resolution of both power and color Doppler imaging. Preliminary investigation has been performed which suggests that contrast enhancement may provide a role in characterization of indeterminate nodules.30,31 Recent prospective evaluation indicates that contrast enhancement can improve specificity, although sensitivity remains similar to unenhanced sonographic evaluation.32
Diagnostic Dilemmas Patients are commonly referred with multiple nodules or advanced multi-nodular goiter. It can be challenging to minimize sampling error by selecting the nodule or nodules which the highest potential for containing atypical cells for biopsy. In addition to nodule selection by evalu-
ating the characteristics outlined in Table I, we would like to re-emphasize the potential for quantitative elastography to provide an objective method of differentiating abnormal tissue. These differences may be entirely occult on grey-scale and color Doppler utrasonography. Another common challenge for both the referring physician and the interventionalist is a non-diagnostic biopsy. Multiple large series at several institutions have documented non-diagnostic FNA rates ranging from 5% to 20%. On follow up surgery or repeat biopsy, occurrence of malignancy in patients with a non-diagnostic FNAB has been demonstrated to range from 5% to 8.5%.33–36 Certainly, evaluation of the FNA samples at the time of the biopsy by pathology staff is one technique to minimize rates of non-diagnostic aspiration biopsies. Even so, given the non-trivial rates of malignancy following nondiagnostic biopsies, either repeat FNA35,36 or core needle biopsy of the lesion34,37,38 has been recommended following an inadequate or non-diagnostic biopsy. Core needle biopsy has been demonstrated to be a more sensitive, albeit more invasive technique.37 Given that the relative risk of a core needle biopsy is significantly less than a thyroidectomy and that a large majority of patients do not ultimately have a malignancy, the operator should not hesitate to consider a core needle biopsy if the alternative is surgical resection.
Acknowledgment NA has Research agreement with Toshiba and DN has Research agreement with Toshiba and Research support from Galil Medical.
References 1. Ezzat S, Sarti DA, Cain DR, Braunstein GD. Thyroid incidentalomas. Prevalence by palpation and ultrasonography. Arch Intern Med 1994 ;154:1838–1840. 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 Off J Am Inst Ultrasound Med 1994;13:87– 90. 3. Woestyn J, Afschrift M, Schelstraete K, Vermeulen A. Demonstration of nodules in the normal thyroid by echography. Br J Radiol 1985;58:1179–1182. 4. Brander A, Viikinkoski P, Nickels J, Kivisaari L. Thyroid gland: US screening in a random adult population. Radiology 1991;181: 683–687. 5. Dean DS, Gharib H. Epidemiology of thyroid nodules. Best Pract Res Clin Endocrinol Metab 2008;22:901–911. 6. Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin 2013;63:11–30. 7. Papini E, Guglielmi R, Bianchini A, et al. Risk of malignancy in nonpalpable thyroid nodules: Predictive value of ultrasound and color-Doppler features. J Clin Endocrinol Metab 2002;87:1941– 1946. 8. Nam-Goong IS, Kim HY, Gong G, et al. Ultrasonography-guided fine-needle aspiration of thyroid incidentaloma: Correlation with pathological findings. Clin Endocrinol (Oxf) 2004;60:21–28. Diagnostic Cytopathology, Vol 41, No 12
1113
Diagnostic Cytopathology DOI 10.1002/dc
AZAR ET AL. 9. Mittendorf EA, Tamarkin SW, McHenry CR. The results of ultrasound-guided fine-needle aspiration biopsy for evaluation of nodular thyroid disease. Surgery 2002;132:648–653; discussion 653–654. 10. Gharib H, Goellner JR. Fine-needle aspiration biopsy of the thyroid: An appraisal. Ann Intern Med 1993;118:282–289. 11. Gharib H. Fine-needle aspiration biopsy of thyroid nodules: Advantages, limitations, and effect. Mayo Clin Proc Mayo Clin 1994;69: 44–49. 12. Danese D, Sciacchitano S, Farsetti A, Andreoli M, Pontecorvi A. Diagnostic accuracy of conventional versus sonography-guided fineneedle aspiration biopsy of thyroid nodules. Thyroid Off J Am Thyroid Assoc 1998;8:15–21. 13. Wang N, Xu Y, Ge C, Guo R, Guo K. Association of sonographically detected calcification with thyroid carcinoma. Head Neck 2006;28:1077–1083. 14. Kim BK, Choi YS, Kwon HJ, et al. Relationship between patterns of calcification in thyroid nodules and histopathologic findings. Endocr J 2013;60:155–160. 15. Frates MC, Benson CB, Doubilet PM, Cibas ES, Marqusee E. Can color Doppler sonography aid in the prediction of malignancy of thyroid nodules? J Ultrasound Med Off J Am Inst Ultrasound Med 2003;22:127–131; quiz 132–134. 16. De Nicola H, Szejnfeld J, Logullo AF, Wolosker AMB, Souza LRMF, Chiferi V Jr. Flow pattern and vascular resistive index as predictors of malignancy risk in thyroid follicular neoplasms. J Ultrasound Med Off J Am Inst Ultrasound Med 2005;24:897–904. 17. Koike E, Noguchi S, Yamashita H, et al. Ultrasonographic characteristics of thyroid nodules: prediction of malignancy. Arch Surg Chic Ill 1960 2001;136:334–337. 18. Kamran SC, Marqusee E, Kim MI, et al. Thyroid nodule size and prediction of cancer. J Clin Endocrinol Metab 2013;98:564–570. 19. Alexander EK, Hurwitz S, Heering JP, et al. Natural history of benign solid and cystic thyroid nodules. Ann Intern Med 2003;138: 315–318. 20. Quadbeck B, Pruellage J, Roggenbuck U, et al. Long-term followup of thyroid nodule growth. Exp Clin Endocrinol Diabetes Off J Ger Soc Endocrinol Ger Diabetes Assoc 2002;110:348–354. 21. Grant CS, Hay ID, Gough IR, McCarthy PM, Goellner JR. Longterm follow-up of patients with benign thyroid fine-needle aspiration cytologic diagnoses. Surgery 1989;106:980–985; discussion 985–986. 22. Frates MC, Benson CB, Charboneau JW, et al. Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement. Radiology 2005;237:794–800. 23. Sippel RS, Elaraj DM, Khanafshar E, Kebebew E, Duh Q-Y, Clark OH. Does the presence of additional thyroid nodules on ultrasound alter the risk of malignancy in patients with a follicular neoplasm of the thyroid? Surgery 2007;142:851–857; discussion 857.e1–2. 24. Heged€us L, Bonnema SJ, Bennedbaek FN. Management of simple nodular goiter: Current status and future perspectives. Endocr Rev 2003;24:102–132.
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25. Mair S, Dunbar F, Becker PJ, Du Plessis W. Fine needle cytology: Is aspiration suction necessary? A study of 100 masses in various sites. Acta Cytol 1989;33:809–813. 26. Santos JE, Leiman G. Nonaspiration fine needle cytology. Application of a new technique to nodular thyroid disease. Acta Cytol 1988;32:353–356. 27. Fagelman D, Chess Q. Nonaspiration fine-needle cytology of the liver: A new technique for obtaining diagnostic samples. AJR Am J Roentgenol 1990;155:1217–1219. 28. De Carvalho GA, Paz-Filho G, Cavalcanti TC, Graf H. Adequacy and diagnostic accuracy of aspiration vs. capillary fine needle thyroid biopsies. Endocr Pathol 2009;20:204–208. 29. Tublin ME, Martin JA, Rollin LJ, Pealer K, Kurs-Lasky M, Ohori NP. Ultrasound-guided fine-needle aspiration versus fine-needle capillary sampling biopsy of thyroid nodules: Does technique matter? J Ultrasound Med Off J Am Inst Ultrasound Med 2007;26: 1697–1701. 30. Molinari F, Mantovani A, Deandrea M, Limone P, Garberoglio R, Suri JS. Characterization of single thyroid nodules by contrastenhanced 3-D ultrasound. Ultrasound Med Biol 2010;36:1616– 1625. 31. Carraro R, Molinari F, Deandrea M, Garberoglio R, Suri JS. Characterization of thyroid nodules by 3-D contrast-enhanced ultrasound imaging. Conf Proc IEEE Eng Med Biol Soc 2008;2008:2229– 2232. 32. Cantisani V, Consorti F, Guerrisi A, et al. Prospective comparative evaluation of quantitative-elastosonography (Q-elastography) and contrast-enhanced ultrasound for the evaluation of thyroid nodules: Preliminary experience. Eur J Radiol 2013;82:1892–1898. 33. Chow LS, Gharib H, Goellner JR, van Heerden JA. Nondiagnostic thyroid fine-needle aspiration cytology: Management dilemmas. Thyroid Off J Am Thyroid Assoc 2001;11:1147–1151. 34. Samir AE, Vij A, Seale MK, et al. Ultrasound-guided percutaneous thyroid nodule core biopsy: Clinical utility in patients with prior nondiagnostic fine-needle aspirate. Thyroid Off J Am Thyroid Assoc 2012;22:461–467. 35. Alexander EK, Heering JP, Benson CB, et al. Assessment of nondiagnostic ultrasound-guided fine needle aspirations of thyroid nodules. J Clin Endocrinol Metab 2002;87:4924–4927. 36. Orija IB, Pi~ neyro M, Biscotti C, Reddy SSK, Hamrahian AH. Value of repeating a nondiagnostic thyroid fine-needle aspiration biopsy. Endocr Pr Off J Am Coll Endocrinol Am Assoc Clin Endocrinol 2007;13:735–742. 37. Yeon JS, Baek JH, Lim HK, et al. Thyroid nodules with initially nondiagnostic cytologic results: The role of core-needle biopsy. Radiology 2013;268:274–280. 38. Na DG, Kim J, Sung JY, et al. Core-needle biopsy is more useful than repeat fine-needle aspiration in thyroid nodules read as nondiagnostic or atypia of undetermined significance by the Bethesda system for reporting thyroid cytopathology. Thyroid Off J Am Thyroid Assoc 2012;22:468–475.
