Abstract
The BRAFV600E mutation test has been more effective in thyroid nodules with suspicious US features than ones without suspicious features. Therefore, we investigated the role of the BRAFV600E mutation as an additional study to cytology in diagnosing a thyroid nodule without suspicious US features. This study was performed at Severance hospital from December 2010 through February 2012. During this period, 2,650 patients with 2,918 nodules underwent FNA with an additional BRAFV600E mutation test. Among them, we excluded thyroid nodules with suspicious US features. Finally, 485 thyroid nodules in 466 patients (mean age 50.3 years; range 9–80 years) were included in this study. We compared the differences between patients with malignant and benign thyroid nodules. We evaluated the detection rates of the BRAFV600E mutation according to the Bethesda System for Reporting Thyroid Cytopathology (BSRTC). There were 60 (60/485, 12.4 %) malignant and 425 (425/485, 87.6 %) benign nodules. The detection rate of the BRAFV600E mutation in thyroid nodules without suspicious US features was only 6.6 % (32/485). Most had malignant cytology (62.5 %, 20/32). For nodules without malignant cytology, only 12 nodules (2.6 %, 12/462) had the BRAF mutation. Among the 12 nodules, nine nodules were suspicious for malignancy on cytology. Additional BRAF mutation analysis shows additional diagnostic value in thyroid nodules with “suspicious for malignant” cytology alone even when the nodules do not show suspicious US features. Therefore, the test should be selectively performed in thyroid nodules without suspicious US features, considering cost-effectiveness as well as diagnostic accuracy.
Similar content being viewed by others
References
S.H. Choi, K.H. Han, J.H. Yoon, H.J. Moon, E.J. Son, J.H. Youk, E. Kim, J.Y. Kwak, Factors affecting inadequate sampling of ultrasound-guided fine-needle aspiration biopsy of thyroid nodules. Clin Endocrinol (Oxf) 74(6), 776–782 (2011)
J.H. Yoon, H.J. Moon, E. Kim, J.Y. Kwak, Inadequate cytology in thyroid nodules: should we repeat aspiration or follow-up? Ann. Surg. Oncol. 18(5), 1282–1289 (2011)
H.J. Moon, E. Son, E.K. Kim, J.H. Yoon, J.Y. Kwak, The diagnostic values of ultrasound and ultrasound-guided fine needle aspiration in subcentimeter-sized thyroid nodules. Ann. Surg. Oncol. 19(1), 52–59 (2012). doi:10.1245/s10434-011-1813-1
J.Y. Kwak, H. Koo, J.H. Youk, M.J. Kim, H.J. Moon, E.J. Son, E. Kim, Value of US correlation of a thyroid nodule with initially benign cytologic results. Radiology 254(1), 292–300 (2010)
E.J. Lee, K.H. Song, D.L. Kim, Y.M. Jang, T.S. Hwang, S.K. Kim, The BRAF(V600E) mutation is associated with malignant ultrasonographic features in thyroid nodules. Clin Endocrinol (Oxf) 75(6), 844–850 (2011). doi:10.1111/j.1365-2265.2011.04154.x
J. Koh, J.R. Choi, K.H. Han, E. Kim, J.H. Yoon, H.J. Moon, J.Y. Kwak, Proper Indication of BRAF(V600E) Mutation Testing in Fine-Needle Aspirates of Thyroid Nodules. PLoS ONE 8(5), e64505–e64505 (2013)
Y.E. Nikiforov, M.N. Nikiforova, Molecular genetics and diagnosis of thyroid cancer. Nature reviews. Endocrinology 7(10), 569–580 (2011)
L. Yip, E. Kebebew, M. Milas, S.E. Carty, T.J. Fahey, S. Parangi, M.A. Zeiger, Y.E. Nikiforov, Summary statement: utility of molecular marker testing in thyroid cancer. Surgery 148(6), 1313–1315 (2010)
L. Yip, C. Farris, A.S. Kabaker, S.P. Hodak, M.N. Nikiforova, K.L. McCoy, M.T. Stang, K.J. Smith, Y.E. Nikiforov, S.E. Carty, Cost impact of molecular testing for indeterminate thyroid nodule fine-needle aspiration biopsies. J. Clin. Endocrinol. Metab. 97(6), 1905–1912 (2012)
G. Troncone, I. Cozzolino, M. Fedele, U. Malapelle, L. Palombini, Preparation of thyroid FNA material for routine cytology and BRAF testing: a validation study. Diagn. Cytopathol. 38(3), 172–176 (2010)
G. Di Benedetto, A. Fabozzi, C.R. Rinaldi, BRAF test and cytological diagnosis with a single fine needle cytology sample. Acta. Cytol. 57(4), 337–340 (2013)
H.J. Moon, E. Kim, W.Y. Chung, J.R. Choi, J.H. Yoon, J.Y. Kwak, Diagnostic value of BRAF(V600E) mutation analysis of thyroid nodules according to ultrasonographic features and the time of aspiration. Ann. Surg. Oncol. 18(3), 792–799 (2011)
S.Y. Nam, B. Han, E.Y. Ko, S.S. Kang, S.Y. Hahn, J. Hwang, M.Y. Nam, J. Kim, J.H. Chung, Y.L. Oh, J.H. Shin, 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 20(3), 273–279 (2010)
Kleiman, D.A., Sporn, M.J., Beninato, T., Crowley, M.J., Nguyen, A., Uccelli, A., Scognamiglio, T., Zarnegar, R., Fahey, T.J.: Preoperative BRAF (V600E) mutation screening is unlikely to alter initial surgical treatment of patients with indeterminate thyroid nodules. Cancer (2012)
Y.E. Nikiforov, N.P. Ohori, S.P. Hodak, S.E. Carty, S.O. LeBeau, R.L. Ferris, L. Yip, R.R. Seethala, M.E. Tublin, M.T. Stang, Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: a prospective analysis of 1056 FNA samples. J. Clin. Endocrinol. Metab. 96(11), 3390–3397 (2011)
A. Colanta, O. Lin, L. Tafe, R. Ghossein, K. Nafa, T. Mitchell, M. Ladanyi, M. Arcila, BRAF mutation analysis of fine-needle aspiration biopsies of papillary thyroid carcinoma: impact on diagnosis and prognosis. Acta. Cytol. 55(6), 563–569 (2011)
H. Chang, H. Lee, S.O. Yoon, H. Kim, A. Kim, B.-H. Kim, BRAFV600E mutation analysis of liquid-based preparation–processed fine needle aspiration sample improves the diagnostic rate of papillary thyroid carcinoma. Hum. Pathol. 43(1), 89–95 (2012)
M.K. Yeo, Z.L. Liang, T. Oh, Y. Moon, S. An, M.K. Kim, K.S. Kim, M. Shong, J.M. Kim, Y.S. Jo, Pyrosequencing cut-off value identifying BRAFV600E mutation in fine needle aspiration samples of thyroid nodules. Clin. Endocrinol. 75(4), 555–560 (2011)
S.-T. Lee, S.W. Kim, C.-S. Ki, J.-H. Jang, J.H. Shin, Y.L. Oh, J.-W. Kim, J.H. Chung, Clinical implication of highly sensitive detection of the BRAF V600E mutation in fine-needle aspirations of thyroid nodules: a comparative analysis of three molecular assays in 4585 consecutive cases in a BRAF V600E mutation-prevalent area. J. Clin. Endocrinol. Metab. 97(7), 2299–2306 (2012)
E.K. Kim, C.S. Park, W.Y. Chung, K.K. Oh, D.I. Kim, J.T. Lee, H.S. Yoo, New sonographic criteria for recommending fine-needle aspiration biopsy of nonpalpable solid nodules of the thyroid. AJR Am. J. Roentgenol. 178(3), 687–691 (2002)
Y.S. Choi, S.W. Hong, J.Y. Kwak, H.J. Moon, E. Kim, Clinical and Ultrasonographic Findings Affecting Nondiagnostic Results upon the Second Fine Needle Aspiration for Thyroid Nodules. Ann. Surg. Oncol. 19(7), 2304–2309 (2012)
J.Y. Song, Y.C. Chu, L. Kim, I.S. Park, J.Y. Han, J.M. Kim, Reclassifying formerly indeterminate thyroid FNAs using the bethesda system reduces the number of inconclusive cases. Acta. Cytol. 56(2), 122–129 (2012). doi:10.1159/000334200
J.Y. Kwak, K.H. Han, J.H. Yoon, E.K. Kim, H.J. Moon, Y.L. Kim, S.J. Park, J.R. Choi, BRAFV600E mutation testing in fine needle aspirates of thyroid nodules: potential value of real-time PCR. Ann. Clin. Lab. Sci. 42(3), 8 (2012)
M. Xing, BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocr. Rev. 28(7), 742–762 (2007)
Y.E. Nikiforov, D.L. Steward, T.M. Robinson-Smith, B.R. Haugen, J.P. Klopper, Z. Zhu, J.A. Fagin, M. Falciglia, K. Weber, M.N. Nikiforova, Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J. Clin. Endocrinol. Metab. 94(6), 2092–2098 (2009). doi:10.1210/jc.2009-0247
C. Romei, L. Fugazzola, E. Puxeddu, F. Frasca, D. Viola, M. Muzza, M. Luisa Nicolosi, C. Giani, V. Cirello, N. Avenia, S. Rossi, P. Vitti, A. Pinchera, R. Elisei, Modifications in the papillary thyroid cancer gene profile over the last 15 Years. J. Clin. Endocrinol. Metab. (2012). doi:10.1210/jc.2012-1269
S.K. Kim, K.-H. Song, S.D. Lim, Y.C. Lim, Y.B. Yoo, J.S. Kim, T.S. Hwang, Clinical and pathological features and the BRAF V600E mutation in patients with papillary thyroid carcinoma with and without concurrent Hashimoto thyroiditis. Thyroid 19(2), 137–141 (2009)
A.J. Adeniran, C. Theoharis, P. Hui, M.L. Prasad, L. Hammers, T. Carling, R. Udelsman, D.C. Chhieng, Reflex BRAF testing in thyroid fine-needle aspiration biopsy with equivocal and positive interpretation: a prospective study. Thyroid 21(7), 717–723 (2011)
L.A. Hassell, E.M. Gillies, S.T. Dunn, Cytologic and molecular diagnosis of thyroid cancers. Cancer Cytopathol. 120(1), 7–17 (2012)
M. Rossi, M. Buratto, S. Bruni, C. Filieri, F. Tagliati, G. Trasforini, R. Rossi, M.D. Beccati, E.C. Degli Uberti, M.C. Zatelli, Role of ultrasonographic/clinical profile, cytology, and BRAF V600E mutation evaluation in thyroid nodule screening for malignancy: a prospective study. J. Clin. Endocrinol. Metab. 97(7), 2354–2361 (2012)
M.C. Zatelli, G. Trasforini, S. Leoni, G. Frigato, M. Buratto, F. Tagliati, R. Rossi, L. Cavazzini, E. Roti, E.C. degli Uberti, BRAF V600E mutation analysis increases diagnostic accuracy for papillary thyroid carcinoma in fine-needle aspiration biopsies. Eur. J. Endocrinol. 161(3), 467–473 (2009)
Y.E. Nikiforov, D.L. Steward, T.M. Robinson-Smith, B.R. Haugen, J.P. Klopper, Z. Zhu, J.A. Fagin, M. Falciglia, K. Weber, M.N. Nikiforova, Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J. Clin. Endocrinol. Metab. 94(6), 2092–2098 (2009)
Kunavisarut T. Diagnostic biomarkers of differentiated thyroid cancer. Endocrine 44(3), 616–622 (2013)
S.K. Kim, D. Kim, H.S. Han, W.S. Kim, W.J. Moon, S.Y. Oh, T.S. Hwang, Pyrosequencing analysis for detection of a BRAFV600E mutation in an FNAB specimen of thyroid nodules. Diagn. Mol. Pathol. 17(2), 118–125 (2008)
K.H. Kim, D.W. Kang, S.H. Kim, I.O. Seong, D.Y. Kang, Mutations of the BRAF gene in papillary thyroid carcinoma in a Korean population. Yonsei Med. J. 45(5), 818–821 (2004)
T.Y. Kim, W.B. Kim, Y.S. Rhee, J.Y. Song, J.M. Kim, G. Gong, S. Lee, S.Y. Kim, S.C. Kim, S.J. Hong, The BRAF mutation is useful for prediction of clinical recurrence in low-risk patients with conventional papillary thyroid carcinoma. Clin. Endocrinol. 65(3), 364–368 (2006)
K.W. Chung, S.K. Yang, G.K. Lee, E.Y. Kim, S. Kwon, S.H. Lee, D.J. Park, H.S. Lee, B.Y. Cho, E.S. Lee, Detection of BRAFV600E mutation on fine needle aspiration specimens of thyroid nodule refines cyto-pathology diagnosis, especially in BRAFV600E mutation-prevalent area. Clin. Endocrinol. 65(5), 660–666 (2006)
J.Y. Kwak, E. Kim, W.Y. Chung, H.J. Moon, M.J. Kim, J.R. Choi, Association of BRAFV600E mutation with poor clinical prognostic factors and US features in Korean patients with papillary thyroid microcarcinoma. Radiology 253(3), 854–860 (2009)
N. Kurtulmus, M. Duren, U. Ince, M. Cengiz Yakicier, O. Peker, O. Aydın, E. Altiok, S. Giray, H. Azizlerli, BRAF(V600E) mutation in Turkish patients with papillary thyroid cancer: strong correlation with indicators of tumor aggressiveness. Endocrine 42(2), 404–410 (2012)
S.Y. Nam, J.H. Shin, B. Han, E.Y. Ko, S.Y. Hahn, J.H. Chung, Preoperative ultrasonographic features of papillary thyroid carcinoma predict biological behavior. J. Clin. Endocrinol. Metab. 98(4), 1476–1482 (2013)
Barbaro, D., Incensati, R.M., Materazzi, G., Boni, G., Grosso, M., Panicucci, E., Lapi, P., Pasquini, C., Miccoli, P.: The BRAF V600E mutation in papillary thyroid cancer with positive or suspected pre-surgical cytological finding is not associated with advanced stages or worse prognosis. Endocrine 1–7 (2013)
S.H. Choi, E.K. Kim, J.Y. Kwak, M.J. Kim, E.J. Son, Interobserver and intraobserver variations in ultrasound assessment of thyroid nodules. Thyroid 20(2), 167–172 (2010). doi:10.1089/thy.2008.0354
G. Kang, E.Y. Cho, J.H. Shin, J.H. Chung, J.W. Kim, Y.L. Oh, Role of BRAFV600E mutation analysis and second cytologic review of fine-needle aspiration for evaluating thyroid nodule. Cancer Cytopathol. 120(1), 44–51 (2012)
Acknowledgments
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0007711).
Conflict of interest
None of the authors has any conflicts of interest to disclose.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Seo, J.Y., Kim, EK. & Kwak, J.Y. Additional BRAF mutation analysis may have additional diagnostic value in thyroid nodules with “suspicious for malignant” cytology alone even when the nodules do not show suspicious US features. Endocrine 47, 283–289 (2014). https://doi.org/10.1007/s12020-013-0150-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-013-0150-5