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Correlation of ThyroSeq Results with Surgical Histopathology in Cytologically Indeterminate Thyroid Nodules

Endocrine Pathology volume 31, pages 377–384 (2020)Cite this article

Abstract

The ThyroSeq next-generation sequencing test refines the risk of malignancy in cytologically indeterminate thyroid nodules. Specific genetic alterations have distinct cancer probabilities and clinical phenotypes. There is limited data on the association between specific genetic alterations and histopathologic features. The aim of this study was to evaluate specific ThyroSeq alterations in prognosticating high-risk histopathologic characteristics. We performed a retrospective single-institution study of all patients diagnosed with indeterminate thyroid nodules (May 2016–December 2019) who had a mutation identified with ThyroSeq v2 or v3 and underwent surgical resection. Specific genetic alterations were correlated with surgical histopathology. The main outcomes were risk of malignancy and structural recurrence risk based on histopathologic features and the 2015 American Thyroid Association (ATA) risk stratification. Of the 78 nodules, 50 (64%) were thyroid cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) on surgical histopathology. Nodules with high-risk TERT or TP53 combination mutations (TERT/TP53) and those with BRAF-like mutations were associated with a 100% probability of cancer and higher rates of extrathyroidal extension and regional nodal involvement than nodules with RAS-like mutations. Among nodules with RAS-like mutations, there was an even distribution between benign, NIFTP, and malignant results, the latter of which were all ATA low risk for structural disease recurrence. Overall, TERT/TP53 and BRAF-like ThyroSeq mutations are associated with an increased cancer probability and risk of recurrence defined by histopathologic features, while RAS-like mutations are associated with lower cancer probability and indolent disease. Individualized management, including extent of surgery, should be considered based on specific genetic alterations found in cytologically indeterminate thyroid nodules.

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References

  1. Pellegriti G, Frasca F, Regalbuto C, Squatrito S, Vigneri R. Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. J Cancer Epidemiol 2013;2013:965212. https://doi.org/10.1155/2013/965212

    Article  PubMed  PubMed Central  Google Scholar 

  2. Cibas ES, Ali SZ. The Bethesda System for Reporting Thyroid Cytopathology. Thyroid 2009;19(11):1159-65.

    Article  PubMed  Google Scholar 

  3. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2016;26(1):1–133. https://doi.org/10.1089/thy.2015.0020

    Article  PubMed  PubMed Central  Google Scholar 

  4. Zhang M, Lin O. Molecular testing of thyroid nodules: a review of current available tests for fine-needle aspiration specimens. Arch Pathol Lab Med 2016;140(12):1338–1344.

    CAS  Article  PubMed  Google Scholar 

  5. Livhits MJ, Kuo EJ, Leung AM, et al. Gene Expression Classifier vs Targeted Next-Generation Sequencing in the Management of Indeterminate Thyroid Nodules. J Clin Endocrinol Metab 2018;103(6):2261-2268.

    Article  PubMed  Google Scholar 

  6. Jug R, Parajuli S, Ahmadi S, Jiang XS. Negative Results on Thyroid Molecular Testing Decrease Rates of Surgery for Indeterminate Thyroid Nodules. Endocr Pathol 2019;30(2):134-137. https://doi.org/10.1007/s12022-019-9571-x

    CAS  Article  PubMed  Google Scholar 

  7. Nikiforov YE, Carty SE, Chiosea SI, et al. Impact of the Multi-Gene ThyroSeq Next-Generation Sequencing Assay on Cancer Diagnosis in Thyroid Nodules with Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance Cytology. Thyroid 2015;25(11):1217–1223. https://doi.org/10.1089/thy.2015.0305

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Borowczyk M, Szczepanek-Parulska E, Olejarz M, et al. Evaluation of 167 Gene Expression Classifier (GEC) and ThyroSeq v2 Diagnostic Accuracy in the Preoperative Assessment of Indeterminate Thyroid Nodules: Bivariate/HROC Meta-analysis [published correction appears in Endocr Pathol. 2019 Feb 8;:]. Endocr Pathol 2019;30(1):8-15. https://doi.org/10.1007/s12022-018-9560-5

    CAS  Article  PubMed  Google Scholar 

  9. Nikiforova MN, Mercurio S, Wald AI, et al. Analytical performance of the ThyroSeq v3 genomic classifier for cancer diagnosis in thyroid nodules. Cancer 2018;124(8):1682–1690. https://doi.org/10.1002/cncr.31245

    CAS  Article  PubMed  Google Scholar 

  10. Steward DL, Carty SE, Sippel RS, et al. Performance of a Multigene Genomic Classifier in Thyroid Nodules With Indeterminate Cytology: A Prospective Blinded Multicenter Study. JAMA Oncol 2019;5(2):204-212.

    Article  PubMed  Google Scholar 

  11. Yip L, Nikiforova MN, Yoo JY, et al. Tumor genotype determines phenotype and disease-related outcomes in thyroid cancer: a study of 1510 patients. Ann Surg 2015;262(3):519–525. https://doi.org/10.1097/SLA.0000000000001420

    Article  PubMed  Google Scholar 

  12. Liu R, Bishop J, Zhu G, Zhang T, Ladenson PW, Xing M. Mortality Risk Stratification by Combining BRAF V600E and TERT Promoter Mutations in Papillary Thyroid Cancer: Genetic Duet of BRAF and TERT Promoter Mutations in Thyroid Cancer Mortality. JAMA Oncol 2017;3(2):202-208.

    Article  PubMed  Google Scholar 

  13. Manzella L, Stella S, Pennisi MS, et al. New Insights in Thyroid Cancer and p53 Family Proteins. Int J Mol Sci. 2017;18(6)

  14. Schneider DF, Cherney Stafford LM, Brys N, et al. Gauging the Extent of Thyroidectomy for Indeterminate Thyroid Nodules: an Oncologic Perspective. Endocr Pract 2017;23(4):442–450. https://doi.org/10.4158/EP161540.OR

    Article  PubMed  PubMed Central  Google Scholar 

  15. Jegerlehner S, Bulliard JL, Aujesky D, et al. Overdiagnosis and overtreatment of thyroid cancer: A population-based temporal trend study. PLoS ONE 2017;12(6):e0179387.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Leite V. The Importance of the 2015 American Thyroid Association Guidelines for Adults with Thyroid Nodules and Differentiated Thyroid Cancer in Minimising Overdiagnosis and Overtreatment of Thyroid Carcinoma. Eur Endocrinol. 2018;14(1):13–14. https://doi.org/10.17925/EE.2018.14.1.13

    Article  PubMed  PubMed Central  Google Scholar 

  17. Olson E, Wintheiser G, Wolfe KM, Droessler J, Silberstein PT. Epidemiology of Thyroid Cancer: A Review of the National Cancer Database, 2000-2013. Cureus 2019;11(2):e4127.

    PubMed  PubMed Central  Google Scholar 

  18. Ohori NP, Landau MS, Carty SE, et al. Benign call rate and molecular test result distribution of ThyroSeq v3. Cancer Cytopathol 2019;127(3):161-168.

    Article  PubMed  Google Scholar 

  19. Romei C, Tacito A, Molinaro E, et al. Clinical, pathological and genetic features of anaplastic and poorly differentiated thyroid cancer: A single institute experience. Oncol Lett 2018;15(6):9174–9182. https://doi.org/10.3892/ol.2018.8470

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Liu R, Xing M. TERT promoter mutations in thyroid cancer. Endocr Relat Cancer 2016;23(3):R143–R155. https://doi.org/10.1530/ERC-15-0533

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Melo M, da Rocha AG, Vinagre J, et al. TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J Clin Endocrinol Metab 2014;99(5):E754–E765. https://doi.org/10.1210/jc.2013-3734

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Pongsapich W, Chongkolwatana C, Poungvarin N, et al. BRAF mutation in cytologically indeterminate thyroid nodules: after reclassification of a variant thyroid carcinoma. Onco Targets Ther 2019;12:1465-1473.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Kebebew E, Weng J, Bauer J, et al. The prevalence and prognostic value of BRAF mutation in thyroid cancer. Ann Surg 2007;246(3):466–471. https://doi.org/10.1097/SLA.0b013e318148563d

    Article  PubMed  PubMed Central  Google Scholar 

  24. Vuong HG, Long NP, Anh NH, et al. Papillary thyroid carcinoma with tall cell features is as aggressive as tall cell variant: a meta-analysis. Endocr Connect 2018;7(12):R286–R293. https://doi.org/10.1530/EC-18-0333

    Article  PubMed  PubMed Central  Google Scholar 

  25. Gupta N, Dasyam AK, Carty SE, et al. RAS mutations in thyroid FNA specimens are highly predictive of predominantly low-risk follicular-pattern cancers. J Clin Endocrinol Metab 2013;98(5):E914–E922. https://doi.org/10.1210/jc.2012-3396

    Article  PubMed  PubMed Central  Google Scholar 

  26. Howell GM, Hodak SP, Yip L. RAS mutations in thyroid cancer. Oncologist 2013;18(8):926–932. https://doi.org/10.1634/theoncologist.2013-0072

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Paulson VA, Shivdasani P, Angell TE, et al. Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features Accounts for More Than Half of “Carcinomas” Harboring RAS Mutations. Thyroid 2017;27(4):506-511.

    CAS  Article  PubMed  Google Scholar 

  28. Zhang Q, Liu BJ, Ren WW, et al. Association between BRAF V600E Mutation and Ultrasound Features in Papillary Thyroid Carcinoma Patients with and without Hashimoto’s Thyroiditis. Sci Rep. 2017;7(1):4899. Published 2017 Jul 7. https://doi.org/10.1038/s41598-017-05153-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Lin ZM, Yan CX, Song Y, et al. The features of contrast enhanced ultrasound and BRAF V600E in papillary thyroid carcinoma. J Thorac Dis. 2019;11(12):5071-5078. https://doi.org/10.21037/jtd.2019.11.78

    Article  PubMed  PubMed Central  Google Scholar 

  30. Kakarmath S, Heller HT, Alexander CA, et al. Clinical, Sonographic, and Pathological Characteristics of RAS-Positive Versus BRAF-Positive Thyroid Carcinoma. J Clin Endocrinol Metab 2016;101(12):4938-4944. https://doi.org/10.1210/jc.2016-2620

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Park JS, Chang JW, Liu L, Jung SN, Koo BS. Clinical implications of microscopic extrathyroidal extension in patients with papillary thyroid carcinoma. Oral Oncol 2017;72:183-187.

    Article  PubMed  Google Scholar 

  32. Janovitz T, Barletta JA. Clinically Relevant Prognostic Parameters in Differentiated Thyroid Carcinoma. Endocr Pathol 2018;29(4):357-364. https://doi.org/10.1007/s12022-018-9548-1

    CAS  Article  PubMed  Google Scholar 

  33. Mete O, Asa SL. Pathological definition and clinical significance of vascular invasion in thyroid carcinomas of follicular epithelial derivation. Mod Pathol 2011;24(12):1545-1552. https://doi.org/10.1038/modpathol.2011.119

    Article  PubMed  Google Scholar 

  34. Bae JS, Kim Y, Jeon S, et al. Clinical utility of TERT promoter mutations and ALK rearrangement in thyroid cancer patients with a high prevalence of the BRAF V600E mutation. Diagn Pathol 2016;11:21. https://doi.org/10.1186/s13000-016-0458-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Tufano RP, Teixeira GV, Bishop J, Carson KA, Xing M. BRAF mutation in papillary thyroid cancer and its value in tailoring initial treatment: a systematic review and meta-analysis. Medicine (Baltimore) 2012;91(5):274-86.

    CAS  Article  Google Scholar 

  36. Medici M, Kwong N, Angell TE, et al. The variable phenotype and low-risk nature of RAS-positive thyroid nodules. BMC Med 2015;13:184. https://doi.org/10.1186/s12916-015-0419-z

    Article  PubMed  PubMed Central  Google Scholar 

  37. Pyo JS, Sohn JH, Kang G. Detection of Tumor Multifocality Is Important for Prediction of Tumor Recurrence in Papillary Thyroid Microcarcinoma: A Retrospective Study and Meta-Analysis. J Pathol Transl Med 2016;50(4):278–286. https://doi.org/10.4132/jptm.2016.03.29

    Article  PubMed  PubMed Central  Google Scholar 

  38. Nikiforov YE. Role of Molecular Markers in Thyroid Nodule Management: Then and Now. Endocr Pract 2017;23(8):979-988.

    Article  PubMed  Google Scholar 

  39. Shrestha RT, Karunamurthy A, Amin K, Nikiforov YE, Caramori ML. Multiple Mutations Detected Preoperatively May Predict Aggressive Behavior of Papillary Thyroid Cancer and Guide Management--A Case Report. Thyroid 2015;25(12):1375-8.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

We thank Dr. Chi-Hong Tseng for performing statistical analysis on the data. We thank Dr. Gregory Brent and Dr. Jeffrey Krane for comments on the project and manuscript.

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Authors and Affiliations

  1. Section of Endocrine Surgery, University of California Los Angeles David Geffen School of Medicine, 10833 Le Conte Ave, Suite 72-228 CHS, Los Angeles, CA, 90095, USA

    Patrick D. Chin, Catherine Y. Zhu, Michael W. Yeh & Masha J. Livhits

  2. Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA, USA

    Dipti P. Sajed & Gregory A. Fishbein

  3. Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA, USA

    Angela M. Leung

  4. Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA

    Angela M. Leung

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  1. Patrick D. Chin
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Contributions

Patrick D. Chin: data curation, formal analysis, investigation, methodology, visualization, writing– original draft, writing– review and editing. Catherine Y. Zhu: conceptualization, data curation, formal analysis, methodology, visualization, writing– original draft, writing– review and editing. Dipti P. Sajed: formal analysis, investigation, visualization, validation, writing– review and editing. Gregory A. Fishbein: formal analysis, investigation, visualization, validation, writing– review and editing. Michael W. Yeh: conceptualization, formal analysis, methodology, project administration, validation, visualization, writing– review and editing. Angela M. Leung: conceptualization, formal analysis, methodology, validation, visualization, writing– review and editing. Masha J. Livhits: conceptualization, data curation, formal analysis, methodology, project administration, validation, visualization, writing– review and editing, supervision.

All authors read and approved the final manuscript.

Corresponding author

Correspondence to Masha J. Livhits.

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The authors declare that they have no conflict of interest.

Ethical Approval

This study was approved by the UCLA Institutional Review Board, and all procedures were in accordance with the ethical standards of the 1964 Helsinki declaration and its later amendments.

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Chin, P.D., Zhu, C.Y., Sajed, D.P. et al. Correlation of ThyroSeq Results with Surgical Histopathology in Cytologically Indeterminate Thyroid Nodules. Endocr Pathol 31, 377–384 (2020). https://doi.org/10.1007/s12022-020-09641-2

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  • DOI: https://doi.org/10.1007/s12022-020-09641-2

Keywords

  • ThyroSeq
  • Indeterminate FNA
  • Thyroid nodule
  • Histopathology
  • Molecular alterations
  • Prognostication