Yonsei Med J.  2014 Jul;55(4):871-878. 10.3349/ymj.2014.55.4.871.

Can Ultrasound Be as a Surrogate Marker for Diagnosing a Papillary Thyroid Cancer? Comparison with BRAF Mutation Analysis

• Seo JY
• Kim EK
• Baek JH
• Shin JH
• Han KH
• Kwak JY

• KMID: 2130809
• DOI: http://doi.org/10.3349/ymj.2014.55.4.871

Abstract

PURPOSE
We investigated the merit of ultrasound (US) features and BRAF(V600E) mutation as an additional study of cytology and compared the diagnostic performances of cytology alone, cytology with US correlation, cytology with BRAF(V600E) mutation, and a combination of cytology, US, and BRAF(V600E) mutation all together.
MATERIALS AND METHODS
This study included 185 patients (mean age, 48.4 years; range 20-77 years) with 191 thyroid nodules who underwent US-guided fine-needle aspiration (FNA) with an additional BRAF(V600E) mutation test. Three radiologists highly experienced in thyroid imaging retrospectively reviewed US images and classified each nodule into two categories (positive for malignancy or negative for malignancy). Interobserver variability (IOV) of US assessment between the three readers was estimated using the generalized kappa statistic of Landis and Koch. We also calculated the diagnostic performances of these studies.
RESULTS
There were 131 cases of malignancy (131/191, 68.6%) and 60 cases of benign nodules (60/191, 31.4%). In terms of IOV of US assessment, the generalized kappa value was 0.242, indicating fair agreement was reached. The combination of cytology with BRAF(V600E) showed higher specificity (100%) and positive predictive value (PPV) (100%) compared to the combination of cytology, BRAF(V600E), and US (specificity 28.3%, 66.7%, 68.3%; PPV 74.6%, 86.6%, 86.8%, respectively; p<0.001). However, cytology with BRAF(V600E) showed lower sensitivity (84.7%) than cytology with BRAF(V600E) and US (96.2%, 98.5%, 95.4%, respectively; p<0.001).
CONCLUSION
Considering the diagnostic performance and low reproducibility of US, the combination of FNA with BRAF(V600E) is the most reliable and objective method for diagnosing thyroid malignancy.

Keyword

Thyroid cancer; BRAF mutation; thyroid ultrasound

MeSH Terms

Adult
Aged
Biological Markers
Biopsy, Fine-Needle
Carcinoma/*diagnosis/genetics/*ultrasonography
Cytodiagnosis
Female
Humans
Male
Middle Aged
Proto-Oncogene Proteins B-raf/*genetics
Retrospective Studies
Thyroid Gland/metabolism/pathology
Thyroid Neoplasms/*diagnosis/genetics/*ultrasonography
Thyroid Nodule/metabolism/pathology
Young Adult
Biological Markers
Proto-Oncogene Proteins B-raf

Figure

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  Fig. 1 Diagram of study group. US, ultrasound; F/U, follow-up.

Reference

1. Yoon JH, Kwak JY, Moon HJ, Kim MJ, Kim EK. The diagnostic accuracy of ultrasound-guided fine-needle aspiration biopsy and the sonographic differences between benign and malignant thyroid nodules 3 cm or larger. Thyroid. 2011; 21:993–1000.

2. Song JY, Chu YC, Kim L, Park IS, Han JY, Kim JM. Reclassifying formerly indeterminate thyroid FNAs using the Bethesda system reduces the number of inconclusive cases. Acta Cytol. 2012; 56:122–129.

3. Moon HJ, Son E, Kim EK, Yoon JH, Kwak JY. The diagnostic values of ultrasound and ultrasound-guided fine needle aspiration in subcentimeter-sized thyroid nodules. Ann Surg Oncol. 2012; 19:52–59.

4. Nikiforov YE, Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol. 2011; 7:569–580.

5. Yip L, Farris C, Kabaker AS, Hodak SP, Nikiforova MN, McCoy KL, et al. Cost impact of molecular testing for indeterminate thyroid nodule fine-needle aspiration biopsies. J Clin Endocrinol Metab. 2012; 97:1905–1912.

6. Lee EJ, Song KH, Kim DL, Jang YM, Hwang TS, Kim SK. The BRAF(V600E) mutation is associated with malignant ultrasonographic features in thyroid nodules. Clin Endocrinol (Oxf). 2011; 75:844–850.

7. Li H, Robinson KA, Anton B, Saldanha IJ, Ladenson PW. Cost-effectiveness of a novel molecular test for cytologically indeterminate thyroid nodules. J Clin Endocrinol Metab. 2011; 96:E1719–E1726.

8. Kwak JY, Han KH, Yoon JH, Kim EK, Moon HJ, Kim YL, et al. BRAFV600E mutation testing in fine needle aspirates of thyroid nodules: potential value of real-time PCR. Ann Clin Lab Sci. 2012; 42:258–265.

9. Kim DW, Lee EJ, Lee JH. Role of ultrasound diagnosis in assessing and managing thyroid nodules with inadequate cytology. AJR Am J Roentgenol. 2011; 197:1213–1219.

10. Kwak JY, Kim EK, Kim HJ, Kim MJ, Son EJ, Moon HJ. How to combine ultrasound and cytological information in decision making about thyroid nodules. Eur Radiol. 2009; 19:1923–1931.

11. Choi YS, Hong SW, Kwak JY, Moon HJ, Kim EK. Clinical and ultrasonographic findings affecting nondiagnostic results upon the second fine needle aspiration for thyroid nodules. Ann Surg Oncol. 2012; 19:2304–2309.

12. Choi SH, Kim EK, Kwak JY, Kim MJ, Son EJ. Interobserver and intraobserver variations in ultrasound assessment of thyroid nodules. Thyroid. 2010; 20:167–172.

13. Kim HG, Kwak JY, Kim EK, Choi SH, Moon HJ. Man to man training: can it help improve the diagnostic performances and interobserver variabilities of thyroid ultrasonography in residents? Eur J Radiol. 2012; 81:e352–e356.

14. Moon WJ, Jung SL, Lee JH, Na DG, Baek JH, Lee YH, et al. Benign and malignant thyroid nodules: US differentiation--multicenter retrospective study. Radiology. 2008; 247:762–770.

15. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009; 19:1167–1214.

16. Gharib H, Papini E, Valcavi R, Baskin HJ, Crescenzi A, Dottorini ME, et al. American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr Pract. 2006; 12:63–102.

17. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977; 33:159–174.

18. Moses W, Weng J, Sansano I, Peng M, Khanafshar E, Ljung BM, et al. Molecular testing for somatic mutations improves the accuracy of thyroid fine-needle aspiration biopsy. World J Surg. 2010; 34:2589–2594.

19. Nikiforov YE, Steward DL, Robinson-Smith TM, Haugen BR, Klopper JP, Zhu Z, et al. Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J Clin Endocrinol Metab. 2009; 94:2092–2098.

20. Romei C, Fugazzola L, Puxeddu E, Frasca F, Viola D, Muzza M, et al. Modifications in the papillary thyroid cancer gene profile over the last 15 years. J Clin Endocrinol Metab. 2012; 97:E1758–E1765.

21. Kim SK, Hwang TS, Yoo YB, Han HS, Kim DL, Song KH, et al. Surgical results of thyroid nodules according to a management guideline based on the BRAF(V600E) mutation status. J Clin Endocrinol Metab. 2011; 96:658–664.

22. Nam SY, Han BK, Ko EY, Kang SS, Hahn SY, Hwang JY, et al. BRAF V600E mutation analysis of thyroid nodules needle aspirates in relation to their ultrasongraphic classification: a potential guide for selection of samples for molecular analysis. Thyroid. 2010; 20:273–279.

23. Moon WJ, Choi N, Choi JW, Kim SK, Hwang TS. BRAF mutation analysis and sonography as adjuncts to fine-needle aspiration cytology of papillary thyroid carcinoma: their relationships and roles. AJR Am J Roentgenol. 2012; 198:668–674.

24. Kim SH, Park CS, Jung SL, Kang BJ, Kim JY, Choi JJ, et al. Observer variability and the performance between faculties and residents: US criteria for benign and malignant thyroid nodules. Korean J Radiol. 2010; 11:149–155.

25. Suh HJ, Moon HJ, Kwak JY, Choi JS, Kim EK. Anaplastic thyroid cancer: ultrasonographic findings and the role of ultrasonography-guided fine needle aspiration biopsy. Yonsei Med J. 2013; 54:1400–1406.