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Usefulness of NRAS codon 61 mutation analysis and core needle biopsy for the diagnosis of thyroid nodules previously diagnosed as atypia of undetermined significance

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Abstract

A repeat fine needle aspiration (FNA) is recommended for thyroid nodules diagnosed as atypia of undetermined significance (AUS) in a previous cytology. We evaluated the utility of NRAS codon 61 (NRAS61) mutation analysis and core needle biopsy (CNB) for the diagnosis of thyroid nodules previously diagnosed as AUS. This study enrolled 236 patients who underwent both NRAS61 mutation analysis and CNB of thyroid nodules previously diagnosed as AUS at cytology. The NRAS61 mutation was detected in 36 nodules and was more frequently detected in the AUS and follicular neoplasm (FN)/suspicious for follicular neoplasm (SFN) categories, as determined by histological analysis of CNB, than in the benign group (p = 0.005). Sixty-one patients underwent surgery, and 29 nodules were finally diagnosed as malignant after surgery. Among 61 patients who underwent surgery, nodules with the NRAS61 mutation (42–65 %) had a significantly higher malignancy rate than nodules with wild-type NRAS61 (7–37 %, p = 0.038). The association between malignancy and the NRAS61 mutation was significant after adjusting for age, sex, nodule size, and histological diagnosis of CNB (p = 0.01). NRAS61 mutation analysis together with CNB could be helpful for arriving at a clinical decision in patients with thyroid nodules showing AUS in a previous cytology.

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References

  1. E.S. Cibas, S.Z. Ali, The Bethesda system for reporting thyroid cytopathology. Thyroid 19(11), 1159–1165 (2009). doi:10.1089/thy.2009.0274

    Article  PubMed  Google Scholar 

  2. L.J. Layfield, M.J. Morton, H.M. Cramer, S. Hirschowitz, Implications of the proposed thyroid fine-needle aspiration category of “follicular lesion of undetermined significance”: a five-year multi-institutional analysis. Diagn. Cytopathol. 37(10), 710–714 (2009). doi:10.1002/dc.21093

    Article  PubMed  Google Scholar 

  3. N.P. Ohori, K.E. Schoedel, Variability in the atypia of undetermined significance/follicular lesion of undetermined significance diagnosis in the Bethesda System for Reporting Thyroid Cytopathology: sources and recommendations. Acta Cytol. 55(6), 492–498 (2011). doi:10.1159/000334218

    Article  PubMed  Google Scholar 

  4. M. Bongiovanni, A. Spitale, W.C. Faquin, L. Mazzucchelli, Z.W. Baloch, The Bethesda system for reporting thyroid cytopathology: a meta-analysis. Acta Cytol. 56(4), 333–339 (2012). doi:10.1159/000339959

    Article  PubMed  Google Scholar 

  5. D.S. Cooper, G.M. Doherty, B.R. Haugen, R.T. Kloos, S.L. Lee, S.J. Mandel, E.L. Mazzaferri, B. McIver, F. Pacini, M. Schlumberger, S.I. Sherman, D.L. Steward, R.M. Tuttle, Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19(11), 1167–1214 (2009). doi:10.1089/thy.2009.0110

    Article  PubMed  Google Scholar 

  6. N. Dincer, S. Balci, A. Yazgan, G. Guney, R. Ersoy, B. Cakir, G. Guler, Follow-up of atypia and follicular lesions of undetermined significance in thyroid fine needle aspiration cytology. Cytopathology 24(6), 385–390 (2013). doi:10.1111/cyt.12021

    Article  CAS  PubMed  Google Scholar 

  7. J.H. Kim, N.K. Kim, Y.L. Oh, H.J. Kim, S.Y. Kim, J.H. Chung, S.W. Kim, The validity of ultrasonography-guided fine needle aspiration biopsy in thyroid nodules 4 cm or larger depends on ultrasonography characteristics. Endocrinol. Metabol. 29, 545–552 (2014)

    Article  Google Scholar 

  8. J.Y. Kwak, Indications for fine needle aspiration in thyroid nodules. Endocrinol. Metabol. 28(2), 81–85 (2013). doi:10.3803/EnM.2013.28.2.81

    Article  Google Scholar 

  9. Z. Baloch, V.A. LiVolsi, P. Jain, R. Jain, I. Aljada, S. Mandel, J.E. Langer, P.K. Gupta, Role of repeat fine-needle aspiration biopsy (FNAB) in the management of thyroid nodules. Diagn. Cytopathol. 29(4), 203–206 (2003). doi:10.1002/dc.10361

    Article  PubMed  Google Scholar 

  10. J. Yang, V. Schnadig, R. Logrono, P.G. Wasserman, Fine-needle aspiration of thyroid nodules: a study of 4703 patients with histologic and clinical correlations. Cancer 111(5), 306–315 (2007). doi:10.1002/cncr.22955

    Article  PubMed  Google Scholar 

  11. K.T. Park, S.H. Ahn, J.H. Mo, Y.J. Park, J. Park do, S.I. Choi, S.Y. Park, Role of core needle biopsy and ultrasonographic finding in management of indeterminate thyroid nodules. Head Neck 33(2), 160–165 (2011). doi:10.1002/hed.21414

    Article  PubMed  Google Scholar 

  12. D.G. Na, J.H. Kim, J.Y. Sung, J.H. Baek, K.C. Jung, H. Lee, H. Yoo, 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 22(5), 468–475 (2012). doi:10.1089/thy.2011.0185

    Article  PubMed  Google Scholar 

  13. P. Lo Gerfo, T. Colacchio, F. Caushaj, C. Weber, C. Feind, Comparison of fine-needle and coarse-needle biopsies in evaluating thyroid nodules. Surgery 92(5), 835–838 (1982)

    CAS  PubMed  Google Scholar 

  14. M. Xing, Molecular pathogenesis and mechanisms of thyroid cancer. Nat. Rev. Cancer 13(3), 184–199 (2013). doi:10.1038/nrc3431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. J.S. Bae, S.K. Choi, S. Jeon, Y. Kim, S. Lee, Y.S. Lee, C.K. Jung, Impact of NRAS mutations on the diagnosis of follicular neoplasm of the thyroid. Int. J. Endocrinol. 2014, 289834 (2014). doi:10.1155/2014/289834

    Article  PubMed  PubMed Central  Google Scholar 

  16. 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, C. Coyne, J.T. Johnson, A.F. Stewart, M.N. Nikiforova, 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. Metabol. 96(11), 3390–3397 (2011). doi:10.1210/jc.2011-1469

    Article  CAS  Google Scholar 

  17. L. Yip, L.I. Wharry, M.J. Armstrong, A. Silbermann, K.L. McCoy, M.T. Stang, N.P. Ohori, S.O. LeBeau, C. Coyne, M.N. Nikiforova, J.E. Bauman, J.T. Johnson, M.E. Tublin, S.P. Hodak, Y.E. Nikiforov, S.E. Carty, A clinical algorithm for fine-needle aspiration molecular testing effectively guides the appropriate extent of initial thyroidectomy. Ann. Surg. 260(1), 163–168 (2014). doi:10.1097/sla.0000000000000215

    Article  PubMed  Google Scholar 

  18. J.H. An, K.H. Song, S.K. Kim, K.S. Park, Y.B. Yoo, J.H. Yang, T.S. Hwang, D.L. Kim, RAS mutations in indeterminate thyroid nodules are predictive of the follicular variant of papillary thyroid carcinoma. Clin. Endocrinol. (2014). doi:10.1111/cen.12579

    Google Scholar 

  19. I.A. Prior, P.D. Lewis, C. Mattos, A comprehensive survey of Ras mutations in cancer. Cancer Res. 72(10), 2457–2467 (2012). doi:10.1158/0008-5472.CAN-11-2612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Y.J. Choi, J.H. Baek, E.J. Ha, H.K. Lim, J.H. Lee, J.K. Kim, D.E. Song, Y.K. Shong, S.J. Hong, Differences in risk of malignancy and management recommendations in subcategories of thyroid nodules with atypia of undetermined significance or follicular lesion of undetermined significance: the role of ultrasound-guided core-needle biopsy. Thyroid 24(3), 494–501 (2014). doi:10.1089/thy.2012.0635

    Article  PubMed  Google Scholar 

  21. J.S. Yeon, J.H. Baek, H.K. Lim, E.J. Ha, J.K. Kim, D.E. Song, T.Y. Kim, J.H. Lee, Thyroid nodules with initially nondiagnostic cytologic results: the role of core-needle biopsy. Radiology 268(1), 274–280 (2013). doi:10.1148/radiol.13122247

    Article  PubMed  Google Scholar 

  22. R.G. Yoon, J.H. Baek, J.H. Lee, Y.J. Choi, M.J. Hong, D.E. Song, J.K. Kim, J.H. Yoon, W.B. Kim, Diagnosis of thyroid follicular neoplasm: fine-needle aspiration versus core-needle biopsy. Thyroid 24(11), 1612–1617 (2014). doi:10.1089/thy.2014.0140

    Article  PubMed  Google Scholar 

  23. H.J. Lee, J. Choi, T.S. Hwang, Y.K. Shong, S.J. Hong, G. Gong, Detection of BRAF mutations in thyroid nodules by allele-specific PCR using a dual priming oligonucleotide system. Am. J. Clin. Pathol. 133(5), 802–808 (2010). doi:10.1309/AJCPO3F2ENKMDTUS

    Article  CAS  PubMed  Google Scholar 

  24. Z.W. Baloch, V.A. LiVolsi, S.L. Asa, J. Rosai, M.J. Merino, G. Randolph, P. Vielh, R.M. DeMay, M.K. Sidawy, W.J. Frable, Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn. Cytopathol. 36(6), 425–437 (2008). doi:10.1002/dc.20830

    Article  PubMed  Google Scholar 

  25. R.S. Mehta, S.E. Carty, N.P. Ohori, S.P. Hodak, C. Coyne, S.O. LeBeau, M.E. Tublin, M.T. Stang, J.T. Johnson, K.L. McCoy, M.N. Nikiforova, Y.E. Nikiforov, L. Yip, Nodule size is an independent predictor of malignancy in mutation-negative nodules with follicular lesion of undetermined significance cytology. Surgery 154(4), 730–736 (2013). doi:10.1016/j.surg.2013.05.015

    Article  PubMed  Google Scholar 

  26. R.M. Tuttle, H. Lemar, H.B. Burch, Clinical features associated with an increased risk of thyroid malignancy in patients with follicular neoplasia by fine-needle aspiration. Thyroid 8(5), 377–383 (1998)

    Article  CAS  PubMed  Google Scholar 

  27. R.E. Goldstein, J.L. Netterville, B. Burkey, J.E. Johnson, Implications of follicular neoplasms, atypia, and lesions suspicious for malignancy diagnosed by fine-needle aspiration of thyroid nodules. Ann. Surg. 235(5), 656–662 (2002)

    Article  PubMed  PubMed Central  Google Scholar 

  28. R.T. Schlinkert, J.A. van Heerden, J.R. Goellner, H. Gharib, S.L. Smith, R.F. Rosales, A.L. Weaver, Factors that predict malignant thyroid lesions when fine-needle aspiration is “suspicious for follicular neoplasm”. Mayo Clin. Proc. 72(10), 913–916 (1997). doi:10.1016/s0025-6196(11)63360-0

    Article  CAS  PubMed  Google Scholar 

  29. H.M. Gweon, E.J. Son, J.H. Youk, J.A. Kim, Thyroid nodules with Bethesda system III cytology: can ultrasonography guide the next step? Ann. Surg. Oncol. 20(9), 3083–3088 (2013). doi:10.1245/s10434-013-2990-x

    Article  PubMed  Google Scholar 

  30. P.W. Rosario, Thyroid nodules with atypia or follicular lesions of undetermined significance (Bethesda Category III): importance of ultrasonography and cytological subcategory. Thyroid 24(7), 1115–1120 (2014). doi:10.1089/thy.2013.0650

    Article  PubMed  Google Scholar 

  31. J.H. Yoon, H.S. Lee, E.K. Kim, H.J. Moon, J.Y. Kwak, A nomogram for predicting malignancy in thyroid nodules diagnosed as atypia of undetermined significance/follicular lesions of undetermined significance on fine needle aspiration. Surgery 155(6), 1006–1013 (2014). doi:10.1016/j.surg.2013.12.035

    Article  PubMed  Google Scholar 

  32. S. Taki, K. Kakuda, K. Kakuma, Y. Annen, S. Katada, R. Yamashita, M. Kosugi, T. Michigishi, N. Tonami, Thyroid nodules: evaluation with US-guided core biopsy with an automated biopsy gun. Radiology 202(3), 874–877 (1997). doi:10.1148/radiology.202.3.9051050

    Article  CAS  PubMed  Google Scholar 

  33. W.J. Choi, J.H. Baek, Role of core needle biopsy for patients with indeterminate, fine-needle aspiration cytology. Endocrine 45(1), 1–2 (2014). doi:10.1007/s12020-013-0071-3

    Article  CAS  PubMed  Google Scholar 

  34. J.I. Son, S.Y. Rhee, J.T. Woo, W.S. Park, J.K. Byun, Y.J. Kim, J.M. Byun, S.O. Chin, S. Chon, S. Oh, S.W. Kim, Y.S. Kim, Insufficient experience in thyroid fine-needle aspiration leads to misdiagnosis of thyroid cancer. Endocrinol. Metabol. 29(3), 293–299 (2014). doi:10.3803/EnM.2014.29.3.293

    Article  Google Scholar 

  35. M.N. Nikiforova, A.I. Wald, S. Roy, M.B. Durso, Y.E. Nikiforov, Targeted next-generation sequencing panel (ThyroSeq) for detection of mutations in thyroid cancer. J. Clin. Endocrinol. Metabol. 98(11), E1852–E1860 (2013). doi:10.1210/jc.2013-2292

    Article  CAS  Google Scholar 

  36. Y.E. Nikiforov, Thyroid carcinoma: molecular pathways and therapeutic targets. Mod. Pathol. 21(Suppl 2), S37–S43 (2008). doi:10.1038/modpathol.2008.10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. J.C. Ricarte-Filho, M. Ryder, D.A. Chitale, M. Rivera, A. Heguy, M. Ladanyi, M. Janakiraman, D. Solit, J.A. Knauf, R.M. Tuttle, R.A. Ghossein, J.A. Fagin, Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res. 69(11), 4885–4893 (2009). doi:10.1158/0008-5472.can-09-0727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. M. Fukahori, A. Yoshida, H. Hayashi, M. Yoshihara, S. Matsukuma, Y. Sakuma, S. Koizume, N. Okamoto, T. Kondo, M. Masuda, Y. Miyagi, The associations between RAS mutations and clinical characteristics in follicular thyroid tumors: new insights from a single center and a large patient cohort. Thyroid 22(7), 683–689 (2012). doi:10.1089/thy.2011.0261

    Article  CAS  PubMed  Google Scholar 

  39. E.K. Jang, D.E. Song, S.Y. Sim, H. Kwon, Y.M. Choi, M.J. Jeon, J.M. Han, W.G. Kim, T.Y. Kim, Y.K. Shong, W.B. Kim, NRAS codon 61 mutation is associated with distant metastasis in patients with follicular thyroid carcinoma. Thyroid 24(8), 1275–1281 (2014). doi:10.1089/thy.2014.0053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. G. Garcia-Rostan, H. Zhao, R.L. Camp, M. Pollan, A. Herrero, J. Pardo, R. Wu, M.L. Carcangiu, J. Costa, G. Tallini, ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer. J. Clin. Oncol. 21(17), 3226–3235 (2003). doi:10.1200/jco.2003.10.130

    Article  CAS  PubMed  Google Scholar 

  41. M.R. Sapio, A. Guerra, V. Marotta, E. Campanile, R. Formisano, M. Deandrea, M. Motta, P.P. Limone, G. Fenzi, G. Rossi, M. Vitale, High growth rate of benign thyroid nodules bearing RET/PTC rearrangements. J. Clin. Endocrinol. Metabol. 96(6), E916–E919 (2011). doi:10.1210/jc.2010-1599

    Article  CAS  Google Scholar 

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Acknowledgments

This study was supported by Grants (No. 2015-633) from the Asan Institute for Life Sciences, Seoul, Korea.

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    Authors and Affiliations

    1. Department of Endocrinology, Dongnam Institute of Radiological and Medical Sciences Cancer Center, Busan, Korea

      Eun Kyung Jang & Eui Young Kim

    2. Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro, 43-gil Songpa-gu, Seoul, 138-736, Korea

      Won Gu Kim, Hyemi Kwon, Yun Mi Choi, Min Ji Jeon, Tae Yong Kim, Young Kee Shong & Won Bae Kim

    3. Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Korea

      Jung Hwan Baek & Jeong Hyun Lee

    4. Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Korea

      Jene Choi & Dong Eun Song

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    1. Eun Kyung Jang
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    Dong Eun Song and Won Bae Kim have contributed equally and should be regarded as co-corresponding authors.

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    Jang, E.K., Kim, W.G., Kim, E.Y. et al. Usefulness of NRAS codon 61 mutation analysis and core needle biopsy for the diagnosis of thyroid nodules previously diagnosed as atypia of undetermined significance. Endocrine 52, 305–312 (2016). https://doi.org/10.1007/s12020-015-0773-9

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