A Gray Zone in Thyroid Fine-Needle Aspiration Cytology: AUS-FLUS

  • Mehmet Ali Koç
  • Seher Demirer
  • Akın Fırat Kocaay


Thyroid nodules are a common finding in the adult population. Fine-needle aspiration biopsy (FNAB), when required, has an important role in the assessment of a thyroid nodule by assisting the triage of patients to surgery or surveillance. However, FNABs which are classified in the Bethesda category 3 (atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS)) are difficult to manage because of the wide spectrum of cytopathologic findings in this category. While the Bethesda System for Reporting Thyroid Cytopathology recommends repeat FNAB for category 3, recent studies recommend molecular testing, if available. And also, surveillance or surgery is recommended especially if repeat FNAB cytology and/or molecular testing is not performed or inconclusive. In conclusion, unlike other categories in Bethesda classification, management of the AUS/FLUS category is still controversial.


AUS FLUS Bethesda category 3 FNAB Thyroid nodule 


  1. 1.
    Kiernan CM, Solórzano CC. Bethesda category III, IV, and V thyroid nodules: can nodule size help predict malignancy? J Am Coll Surg. 2017;225:77–82.CrossRefGoogle Scholar
  2. 2.
    Russ G, Leboulleux S, Leenhardt L, Hegedus L. Thyroid incidentalomas: epidemiology, risk stratification with ultrasound and workup. Eur Thyroid J. 2014;3:154–63.CrossRefGoogle Scholar
  3. 3.
    Polyzos SA, Kita M, Avramidis A. Thyroid stepwise diagnosis and management. Hormones. 2007;6:101–19.CrossRefGoogle Scholar
  4. 4.
    Cibas ES, Ali SZ, NCI Thyroid FNA State of the Science Conference. The Bethesda system for reporting thyroid cytopathology. Am J Clin Pathol. 2009;132:658–65.CrossRefGoogle Scholar
  5. 5.
    Estrada Muñoz L, Díaz Del Arco C, Ortega Medina L, Fernández Aceñero MJ. Thyroid atypia/follicular lesion of undetermined significance: attitudes towards the diagnosis of Bethesda system III nodules. Acta Cytol. 2017;61:21–6.CrossRefGoogle Scholar
  6. 6.
    Cohen O, Tzelnick S, Lahav Y, Schindel D, Halperin D, Yehuda M. Selection of atypia/follicular lesion of unknown significance patients for surgery versus active surveillance, without using genetic testing: a single institute experience, prospective analysis, and recommendations. Thyroid. 2017;27:928–35.CrossRefGoogle Scholar
  7. 7.
    Kholova I, Ludvikova M. Thyroid atypia of undetermined significance or follicular lesion of undetermined significance: an indispensable Bethesda 2010 diagnostic category or waste garbage? Acta Cytol. 2014;58:319–29.CrossRefGoogle Scholar
  8. 8.
    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;96:658–64.CrossRefGoogle Scholar
  9. 9.
    Carr R, Ustun B, Chhieng D, Schofield K, Theoharis C, Hammers L, et al. Radiologic and clinical predictors of malignancy in the follicular lesion of undetermined significance of the thyroid. Endocr Pathol. 2013;24:62–8.CrossRefGoogle Scholar
  10. 10.
    Crowe A, Linder A, Hameed O, Salih C, Roberson J, Gidley J, et al. The impact of implementation of the Bethesda system for reporting thyroid cytopathology on the quality of reporting, “risk” of malignancy, surgical rate, and rate of frozen sections requested for thyroid lesions. Cancer Cytopathol. 2011;119:315–21.CrossRefGoogle Scholar
  11. 11.
    Bongiovanni M, Spitale A, Faquin WC, Mazzucchelli L, Baloch ZW. The Bethesda system for reporting thyroid cytopathology: a meta-analysis. Acta Cytol. 2012;56:333–9.CrossRefGoogle Scholar
  12. 12.
    Topaloglu O, Baser H, Cuhaci FN, Sungu N, Yalcin A, Ersoy R, et al. Malignancy is associated with microcalcification and higher AP/T ratio in ultrasonography, but not with Hashimoto's thyroiditis in histopathology in patients with thyroid nodules evaluated as Bethesda Category III (AUS/FLUS) in cytology. Endocrine. 2016;54:156–68.CrossRefGoogle Scholar
  13. 13.
    Gocun PU, Karakus E, Bulutay P, Akturk M, Akin M, Poyraz A. What is the malignancy risk for atypia of undetermined significance?. Three years’ experience at a university hospital in Turkey. Cancer Cytopathol. 2014;122:604–10.CrossRefGoogle Scholar
  14. 14.
    Park HJ, Moon JH, Yom CK, Kim KH, Choi JY, Choi SI, et al. Thyroid “atypia of undetermined significance” with nuclear atypia has high rates of malignancy and BRAF mutation. Cancer Cytopathol. 2014;122:512–20.CrossRefGoogle Scholar
  15. 15.
    Turkyilmaz S, Ulusahin M, Celebi B, Cekic AB, Mungan S, Kucuktulu U, et al. Thyroid nodules classified as atypia or follicular lesions of undetermined significance deserve further research: analysis of 305 surgically confirmed nodules. Cytopathology. 2017;28:391–9.CrossRefGoogle Scholar
  16. 16.
    Vanderlaan PA, Krane JF, Cibas ES. The frequency of ‘atypia of undetermined significance’ interpretations for thyroid fine-needle aspirations is negatively correlated with histologically proven malignant outcomes. Acta Cytol. 2011;55:512–7.CrossRefGoogle Scholar
  17. 17.
    Rosario PW, Calsolari MR. Importance of cytological subclassification of thyroid nodules with Bethesda category III cytology (AUS/FLUS) into architectural atypia only and nuclear atypia: a prospective study. Diagn Cytopathol. 2017;45(7):604.CrossRefGoogle Scholar
  18. 18.
    Gan TR, Nga ME, Lum JH, Wong WM, Tan WB, Parameswaran R, et al. Thyroid cytology-nuclear versus architectural atypia within the "atypia of undetermined significance/follicular lesion of undetermined significance" Bethesda category have significantly different rates of malignancy. Cancer. 2017;125:245–56.Google Scholar
  19. 19.
    Chandra S, Chandra H, Bisht SS. Malignancy rate in thyroid nodules categorized as atypia of undetermined significance or follicular lesion of undetermined significance: an institutional experience. J Cytol. 2017;34:144–8.CrossRefGoogle Scholar
  20. 20.
    Kim SD, Han SH, Jeong WJ, Kim H, Ahn SH. Differences in clinical features between subcategories of “atypia/follicular lesion of undetermined significance”. Endocr Pathol. 2017;28:247–52.CrossRefGoogle Scholar
  21. 21.
    Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, 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;26:1–133.CrossRefGoogle Scholar
  22. 22.
    Nikiforov YE, Ohori NP, Hodak SP, Carty SE, LeBeau SO, Ferris RL, et al. 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. 2011;96:3390–7.CrossRefGoogle Scholar
  23. 23.
    Cantara S, Capezzone M, Marchisotta S, Capuano S, Busonero G, Toti P, et al. Impact of proto-oncogene mutation detection in cytological specimens from thyroid nodules improves the diagnostic accuracy of cytology. J Clin Endocrinol Metab. 2010;95:1365–9.CrossRefGoogle Scholar
  24. 24.
    Labourier E, Shifrin A, Busseniers AE, Lupo MA, Manganelli ML, Andruss B, et al. Molecular testing for miRNA, mRNA, and DNA on fine-needle aspiration improves the preoperative diagnosis of thyroid nodules with indeterminate cytology. J Clin Endocrinol Metab. 2015;100:2743–50.CrossRefGoogle Scholar
  25. 25.
    Nikiforov YE, Carty SE, Chiosea SI, Coyne C, Duvvuri U, Ferris RL, 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;25:1217–23.CrossRefGoogle Scholar
  26. 26.
    Lithwick-Yanai G, Dromi N, Shtabsky A, Morgenstern S, Strenov Y, Feinmesser M, et al. Multicentre validation of a microRNA-based assay for diagnosing indeterminate thyroid nodules utilising fine needle aspirate smears. J Clin Pathol. 2017;70:500–7.CrossRefGoogle Scholar
  27. 27.
    Wu JX, Lam R, Levin M, Rao J, Sullivan PS, Yeh MW. Effect of malignancy rates on cost-effectiveness of routine gene expression classifier testing for indeterminate thyroid nodules. Surgery. 2016;159:118–26.CrossRefGoogle Scholar
  28. 28.
    Kwak JY, Han KH, Yoon JH, Moon HJ, Son EJ, Park SH, et al. Thyroid imaging reporting and data system for US features of nodules: a step in establishing better stratification of cancer risk. Radiology. 2011;260:892–9.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  • Mehmet Ali Koç
    • 1
  • Seher Demirer
    • 1
  • Akın Fırat Kocaay
    • 1
  1. 1.Ankara University, School of Medicine, Department of SurgeryAnkaraTurkey

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