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Clinical endocrinology
04, 2022;96 (4): 637-645.

Utility of mutational analysis for risk stratification of indeterminate thyroid nodules in a real-world setting.

Vanessa Torrecillas, Anu Sharma, Kaden Neuberger, Dev Abraham
Author Information
  1. Vanessa Torrecillas: Department of Otolaryngology-Head and Neck Surgery, University of Utah, Salt Lake City, Utah, USA. ORCID
  2. Anu Sharma: Department of Internal Medicine, Endocrinology, University of Utah, Salt Lake City, Utah, USA. ORCID
  3. Kaden Neuberger: School of Medicine, University of Utah, Salt Lake City, Utah, USA. ORCID
  4. Dev Abraham: Department of Internal Medicine, Endocrinology, University of Utah, Salt Lake City, Utah, USA. ORCID
PMID: 34605038 DOI: 10.1111/cen.14601

Abstract

OBJECTIVE: American Thyroid Association (ATAn) 2015 guidelines recommend repeat fine-needle aspiration with molecular marker profiling (MMP) or diagnostic lobectomy in thyroid nodules yielding atypia of unknown significance/follicular lesion of unknown significance (AUS/FLUS) or follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) cytology. Our objective is to describe the molecular profiles and histological correlates of these cytologically indeterminate nodules (CIN) to aid risk stratification.
DESIGN: Retrospective chart review.
PATIENTS: Adults with CIN that underwent MMP from 2017 to 2020.
MEASUREMENTS: Pearsons' χ , Fisher's exact test, nonparametric testing and multiple regression analysis were performed.
RESULTS: A total of 89 CIN underwent mutational analysis. Of 55% (n = 49) were Bethesda class III AUS/FLUS and 45% (n = 40) were Bethesda class IV FN/SFN. The US phenotype of a CIN was isoechoic (53%) or hypoechoic (32%) with well-defined margins (98%), absence of calcifications (75%) and mildly increased internal vascularity (70%). A total of 84% and 87% of nodules were classified as mild/moderate or low/intermediate risk per the Thyroid Imaging Reporting and Data System and ATA classifications, respectively. Based on the Thyroseq patient management resource, 6.7% (n = 6) of nodules had a high predicted probability of cancer (≥95%), 41.6% (n = 37) were intermediate probability (40%-94%) and 51.7% (n = 46) were low probability (<40%). MMP revealed positive mutations in 45% (n = 40) of nodules, with 71% demonstrating RAS mutations. Of the nodules that underwent resection (n = 38), 39% (n = 15) had malignant pathology. Increasing the threshold to recommend surgical resection to a Thyroseq predicted probability of cancer to ≥50%, had a 100% sensitivity and 65% specificity for detecting malignant nodules (area under the ROC curve: 0.86). The positive predictive value was 37% and the negative predictive value was 100%.
CONCLUSION: US phenotypes of CIN nodules were variable and did not aid in differentiating malignant from benign nodules. Of the CIN nodules with a positive MMP, most were RAS and had a benign pathology. With the exception of high-risk genetic markers for malignancy, the threshold to recommend surgical resection should be raised for CIN. Further studies to improve risk stratification in these nodules are required.

Keywords

molecular markers thyroid thyroid neoplasm thyroid nodule ultrasound

References

  1. Ohori NP, Schoedel KE. 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. 2011;55(6):492-498. https://doi.org/10.1159/000334218
  2. 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
  3. 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
  4. Remonti LR, Kramer CK, Leitão CB, Pinto LC, Gross JL. Thyroid ultrasound features and risk of carcinoma: a systematic review and meta-analysis of observational studies. Thyroid. 2015;25(5):538-550. https://doi.org/10.1089/thy.2014.0353
  5. Lee JH, Han K, Kim EK, et al. Risk stratification of thyroid nodules with atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) cytology using ultrasonography patterns defined by the 2015 ATA guidelines. Ann Otol Rhinol Laryngol. 2017;126(9):625-633. https://doi.org/10.1177/0003489417719472
  6. Fukunari N, Nagahama M, Sugino K, Mimura T, Ito K. Clinical evaluation of color Doppler imaging for the differential diagnosis of thyroid follicular lesions. World J Surg. 2004;28(12):1261-1265. https://doi.org/10.1007/s00268-004-7597-8
  7. Yoon JH, Kwon HJ, Kim EK, Moon HJ, Kwak JY. Subcategorization of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS): a study applying Thyroid Imaging Reporting and Data System (TIRADS). Clin Endocrinol. 2016;85(2):275-282. https://doi.org/10.1111/cen.12987
  8. Tessler FN, Middleton WD, Grant EG, et al. ACR Thyroid Imaging, Reporting and Data System (TI-RADS): white paper of the ACR TI-RADS Committee. J Am Coll Radiol. 2017;14(5):587-595. https://doi.org/10.1016/j.jacr.2017.01.046
  9. Patient Management ThyroSeq Thyroid Genomic Classifier. UPMC; 2017.
  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. https://doi.org/10.1001/jamaoncol.2018.4616
  11. Xing M. Clinical utility of RAS mutations in thyroid cancer: a blurred picture now emerging clearer. BMC Med. 2016;14:12. https://doi.org/10.1186/s12916-016-0559-9
  12. Moon WJ, Jung SL, Lee JH, et al. Benign and malignant thyroid nodules: US differentiation-multicenter retrospective study. Radiology. 2008;247(3):762-770. https://doi.org/10.1148/radiol.2473070944
  13. Jun P, Chow LC, Jeffrey RB. The sonographic features of papillary thyroid carcinomas: pictorial essay. Ultrasound Q. 2005;21(1):39-45.
  14. Chan BK, Desser TS, McDougall IR, Weigel RJ, Jeffrey RB. Common and uncommon sonographic features of papillary thyroid carcinoma. J Ultrasound Med. 2003;22(10):1083-1090. https://doi.org/10.7863/jum.2003.22.10.1083
  15. Shao J, Shen Y, Lü J, Wang J. Ultrasound scoring in combination with ultrasound elastography for differentiating benign and malignant thyroid nodules. Clin Endocrinol. 2015;83(2):254-260. https://doi.org/10.1111/cen.12589
  16. Durante C, Grani G, Lamartina L, Filetti S, Mandel SJ, Cooper DS. The diagnosis and management of thyroid nodules: a review. JAMA. 2018;319(9):914-924. https://doi.org/10.1001/jama.2018.0898
  17. Brito JP, Gionfriddo MR, Al Nofal A, et al. The accuracy of thyroid nodule ultrasound to predict thyroid cancer: systematic review and meta-analysis. J Clin Endocrinol Metab. 2014;99(4):1253-1263. https://doi.org/10.1210/jc.2013-2928
  18. Rosario PW, Silva AL, Borges MA, Calsolari MR. Is Doppler ultrasound of additional value to gray-scale ultrasound in differentiating malignant and benign thyroid nodules? Arch Endocrinol Metab. 2015;59(1):79-83. https://doi.org/10.1590/2359-3997000000014
  19. Moon HJ, Kwak JY, Kim MJ, Son EJ, Kim EK. Can vascularity at power Doppler US help predict thyroid malignancy? Radiology. 2010;255(1):260-269. https://doi.org/10.1148/radiol.09091284
  20. Kaliszewski K, Diakowska D, Wojtczak B, Forkasiewicz Z. Evaluation of selected ultrasound features of thyroid nodules with atypia of undetermined significance/follicular lesion of undetermined significance for the Bethesda reporting system for thyroid cytology. Cancer Manag Res. 2018;10:2223-2229. https://doi.org/10.2147/CMAR.S168409
  21. Matthey-Gie ML, Walsh SM, O'Neill AC, et al. Ultrasound predictors of malignancy in indeterminate thyroid nodules. Ir J Med Sci. 2014;183(4):633-637. https://doi.org/10.1007/s11845-013-1065-0
  22. 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
  23. 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
  24. 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
  25. Rossi M, Buratto M, Tagliati F, et al. Relevance of BRAF(V600E) mutation testing versus RAS point mutations and RET/PTC rearrangements evaluation in the diagnosis of thyroid cancer. Thyroid. 2015;25(2):221-228. https://doi.org/10.1089/thy.2014.0338
  26. Cibas ES, Ali SZ. The Bethesda system for reporting thyroid cytopathology. Thyroid. 2009;19(11):1159-1165. https://doi.org/10.1089/thy.2009.0274
  27. Clinkscales W, Ong A, Nguyen S, Harruff EE, Gillespie MB. Diagnostic value of RAS mutations in indeterminate thyroid nodules. Otolaryngol Head Neck Surg. 2017;156(3):472-479. https://doi.org/10.1177/0194599816685697
  28. Krasner JR, Alyouha N, Pusztaszeri M, et al. Molecular mutations as a possible factor for determining extent of thyroid surgery. J Otolaryngol Head Neck Surg. 2019;48(1):51. https://doi.org/10.1186/s40463-019-0372-5
  29. Xing M. Genetic-guided risk assessment and management of thyroid cancer. Endocrinol Metab Clin North Am. 2019;48(1):109-124. https://doi.org/10.1016/j.ecl.2018.11.007
  30. Dobrescu R, Badiu C. Actualities in genetics of differentiated thyroid cancer. Acta Endocrinol. 2020;16(1):118-120. https://doi.org/10.4183/aeb.2020.118
  31. Chung JH. BRAF and TERT promoter mutations: clinical application in thyroid cancer. Endocr J. 2020;67(6):577-584. https://doi.org/10.1507/endocrj.EJ20-0063
  32. Huang M, Yan C, Xiao J, Wang T, Ling R. Relevance and clinicopathologic relationship of BRAF V600E, TERT and NRAS mutations for papillary thyroid carcinoma patients in Northwest China. Diagn Pathol. 2019;14(1):74. https://doi.org/10.1186/s13000-019-0849-6

MeSH Term

Humans
Adenocarcinoma, Follicular
Retrospective Studies
Risk Assessment
Thyroid Neoplasms
Thyroid Nodule
Journal Article

Word Cloud

Created with Highcharts 10.0.0nodulesCINthyroidMMPriskprobabilityrecommendmolecularstratificationunderwentanalysispositiveresectionmalignantThyroidunknownAUS/FLUSfollicularneoplasmFN/SFNindeterminateaidtotalmutationalBethesdaclass45%n = 40USThyroseq7%predictedcancermutationsRASpathologythresholdsurgical100%predictivevaluebenignmarkersOBJECTIVE:AmericanAssociationATAn2015guidelinesrepeatfine-needleaspirationmarkerprofilingdiagnosticlobectomyyieldingatypiasignificance/follicularlesionsignificanceneoplasm/suspiciouscytologyobjectivedescribeprofileshistologicalcorrelatescytologicallyDESIGN:RetrospectivechartreviewPATIENTS:Adults20172020MEASUREMENTS:Pearsons'χFisher'sexacttestnonparametrictestingmultipleregressionperformedRESULTS:8955%n = 49IIIIVphenotypeisoechoic53%hypoechoic32%well-definedmargins98%absencecalcifications75%mildlyincreasedinternalvascularity70%84%87%classifiedmild/moderatelow/intermediateperImagingReportingDataSystemATAclassificationsrespectivelyBasedpatientmanagementresource6n = 6high≥95%416%n = 37intermediate40%-94%51n = 46low<40%revealed71%demonstratingn = 3839%n = 15Increasing≥50%sensitivity65%specificitydetectingareaROCcurve:08637%negativeCONCLUSION:phenotypesvariabledifferentiatingexceptionhigh-riskgeneticmalignancyraisedstudiesimproverequiredUtilityreal-worldsettingnoduleultrasound

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