Atypical Cells of Undetermined Significance/Follicular Lesion of Undetermined Significance

  • Rana S. HodaEmail author
  • Rema Rao
  • Theresa Scognamiglio


Thyroid FNA has reduced the rate of unnecessary surgeries for benign thyroid nodules. High negative predictive value (NPV) of a benign FNA diagnosis has made it a valuable initial test for thyroid nodules.


Atypical cell of undetermined significance Follicular lesion of undetermined significance Hürthle cell lesions Hürthle cell lesions NIFTP Papillary thyroid carcinoma Histiocytoid cells Atypical cyst-lining cells Histiocytoid cells Molecular tests Immunocytochemistry 

Suggested Reading

  1. 1.
    Absher KJ, Truong LD, Khurana KK, Ramzy I. Parathyroid cytology: avoiding diagnostic pitfalls. Head Neck. 2002;24:157–64.CrossRefGoogle Scholar
  2. 2.
    Ali SZ, Cibas ES, editors. The Bethesda System for reporting thyroid cytopathology; definitions, criteria, and explanatory notes. 2nd ed. Cham: Springer International Publishing AG; 2018.Google Scholar
  3. 3.
    Ali SZ, Nayar R, Krane JF, Westra WH. Atlas of thyroid cytopathology with histopathologic correlations. New York: Demos Medical Publishing; 2014.Google Scholar
  4. 4.
    Baca SC, Wong KS, Strickland KC, Heller HT, Kim MI, Barletta JA, et al. Qualifiers of atypia in the cytologic diagnosis of thyroid nodules are associated with different Afirma gene expression classifier results and clinical outcomes. Cancer Cytopathol. 2017;125:313–22. Scholar
  5. 5.
    Brandler TC, Cho M, Wei XJ, Simms A, Levine P, Hernandez O, et al. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features: an interobserver study of key cytomorphological features from a large academic medical centre. Cytopathology. 2019;30:39–45. Scholar
  6. 6.
    Cibas ES, Ali SZ. The 2017 Bethesda System for reporting thyroid cytopathology. Thyroid. 2017;27:1341–6. Scholar
  7. 7.
    Cibas ES, Baloch ZW, Fellegara G, LiVolsi VA, Raab SS, Rosai J, et al. A prospective assessment defining the limitations of thyroid nodule pathologic evaluation. Ann Intern Med. 2013;159:325–32. Scholar
  8. 8.
    Choong KC, Khiyami A, Tamarkin SW, McHenry CR. Fine-needle aspiration biopsy of thyroid nodules: Is routine ultrasound-guidance necessary? Surgery. 2018;164:789–94. Scholar
  9. 9.
    Dincer N, Balci S, Yazgan A, Guney G, Ersoy R, Cakir B, et al. Follow-up of atypia and follicular lesions of undetermined significance in thyroid fine needle aspiration cytology. Cytopathology. 2013;24:385–90. Scholar
  10. 10.
    Eisa N, Khan A, Akhter M, Fensterwald M, Saleem S, Fananapazir G, et al. Both ultrasound features and nuclear atypia are associated with malignancy in thyroid nodules with atypia of undetermined significance. Ann Surg Oncol. 2018;25:3913–8. Scholar
  11. 11.
    Faquin WC, Cibas ES, Renshaw AA. “Atypical” cells in fine-needle aspiration biopsy specimens of benign thyroid cysts. Cancer. 2005;105:71–9.CrossRefGoogle Scholar
  12. 12.
    Faquin WC, Wong LQ, Afrogheh AH, Ali SZ, Bishop JA, Bongiovanni M, et al. Impact of reclassifying noninvasive follicular variant of papillary thyroid carcinoma on the risk of malignancy in The Bethesda System for Reporting Thyroid Cytopathology. Cancer Cytopathol. 2016;124:181–7. Scholar
  13. 13.
    Fischer AH, Clayton AC, Bentz JS, Wasserman PG, Henry MR, Souers RJ, et al. Performance differences between conventional smears and liquid-based preparations of thyroid fine-needle aspiration samples: analysis of 47,076 responses in the College of American Pathologists Interlaboratory Comparison Program in Non-Gynecologic Cytology. Arch Pathol Lab Med. 2013;137:26–31. Scholar
  14. 14.
    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 Cytopathol. 2017;125:245–56. Scholar
  15. 15.
    Geramizadeh B, Bos-Hagh S, Maleki Z. Cytomorphologic, imaging, molecular findings, and outcome in thyroid Follicular Lesion of Undetermined Significance/Atypical Cell of Undetermined Significance (AUS/FLUS): a mini-review. Acta Cytol. 2019;63:1–9. Scholar
  16. 16.
    Gerhard R, Boerner SL. Evaluation of indeterminate thyroid cytology by second-opinion diagnosis or repeat fine-needle aspiration: which is the best approach? Acta Cytol. 2015;59:43–50. Scholar
  17. 17.
    Godoi Cavalheiro B, Kober Nogueira Leite A, Luongo de Matos L, Palermo Miazaki A, Ientile JM, Kulcsar MA, Cernea CR. Malignancy rates in thyroid nodules classified as Bethesda categories III and IV: retrospective data from a tertiary center. Int J Endocrinol Metab. 2017;16:e12871. Scholar
  18. 18.
    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. Scholar
  19. 19.
    Hoda RS. Non-gynecologic cytology on liquid-based preparations: a morphologic review of facts and artifacts. Diagn Cytopathol. 2007;35:621–34.CrossRefGoogle Scholar
  20. 20.
    Hoda RS, VandenBussche C, Hoda SA. Diagnostic liquid-based cytology. New York: Springer; 2017.CrossRefGoogle Scholar
  21. 21.
    Hang JF, Westra WH, Zhou AG, Cooper DS, Ali SZ. The impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features on the rate of malignancy for atypia of undetermined significance subcategories. Cancer Cytopathol. 2018;126:309–16. Scholar
  22. 22.
    Jan IS, Lee YT, Wang CM, Cheng TY, Wang CY, Chang TC, et al. The surgery and repeat aspiration outcomes of the atypia of undetermined significance/follicular lesion of undetermined significance category in The Bethesda System for Reporting Thyroid Cytopathology. Asian J Surg. 2019;42:144–7. Scholar
  23. 23.
    Jo VY, Stelow EB, Dustin SM, Hanley KZ. Malignancy risk for fine-needle aspiration of thyroid lesions according to the Bethesda System for Reporting Thyroid Cytopathology. Am J Clin Pathol. 2010;134:450–6. Scholar
  24. 24.
    Jug RC, Datto MB, Jiang XS. Molecular testing for indeterminate thyroid nodules: performance of the Afirma gene expression classifier and ThyroSeq panel. Cancer Cytopathol. 2018;126:471–80. Scholar
  25. 25.
    Jung YY, Jung S, Lee HW, Oh YL. Significance of subcategory atypia of undetermined significance/follicular lesion of undetermined significance showing both cytologic and architectural atypia in thyroid aspiration cytology. Acta Cytol. 2015;59:370–6. Scholar
  26. 26.
    Khalil AB, Dina R, Meeran K, Bakir AM, Naqvi S, Al Tikritti A, et al. Indeterminate thyroid nodules: a pragmatic approach. Eur Thyroid J. 2018;7:39–43. Scholar
  27. 27.
    Kim Y, Choi KR, Chae MJ, Shin BK, Kim HK, Kim A, et al. Stability of DNA, RNA, cytomorphology, and immunoantigenicity in residual ThinPrep specimens. APMIS. 2013;121:1064–72. Scholar
  28. 28.
    Kim SJ, Roh J, Baek JH, Hong SJ, Shong YK, Kim WB, et al. Risk of malignancy according to sub-classification of the atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) category in the Bethesda System for Reporting Thyroid Cytopathology. Cytopathology. 2017;28:65–73. Scholar
  29. 29.
    Krane JF, Cibas ES, Alexander EK, Paschke R, Eszlinger M. Molecular analysis of residual ThinPrep material from thyroid FNAs increases diagnostic sensitivity. Cancer Cytopathol. 2015;123:356–61. Scholar
  30. 30.
    Krauss EA, Mahon M, Fede JM, Zhang L. Application of the Bethesda Classification for thyroid fine-needle aspiration: Institutional experience and meta-analysis. Arch Pathol Lab Med. 2016;140:1121–31. Scholar
  31. 31.
    Lauria Pantano A, Maddaloni E, Briganti SI, Beretta Anguissola G, Perrella E, Taffon C, et al. Differences between ATA, AACE/ACE/AME and ACR TI-RADS ultrasound classifications performance in identifying cytological high-risk thyroid nodules. Eur J Endocrinol. 2018;178:595–603. Scholar
  32. 32.
    Lee JH, Han K, Kim EK, Moon HJ, Yoon JH, Park VY, 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;126:625–33. Scholar
  33. 33.
    Lim JXY, Nga ME, Chan DKH, Tan WB, Parameswaran R, Ngiam KY. Subclassification of Bethesda Atypical and Follicular Neoplasm categories according to nuclear and architectural atypia improves discrimination of thyroid malignancy risk. Thyroid. 2018;28:511–21. Scholar
  34. 34.
    Luu MH, Fischer AH, Stockl TJ, Pisharodi L, Owens CL. Atypical follicular cells with equivocal features of papillary thyroid carcinoma is not a low-risk cytologic diagnosis. Acta Cytol. 2011;55:526–30. Scholar
  35. 35.
    Michael CW, Hunter B. Interpretation of fine-needle aspirates processed by the ThinPrep technique: cytologic artifacts and diagnostic pitfalls. Diagn Cytopathol. 2000;23:6–13.CrossRefGoogle Scholar
  36. 36.
    Michael CW, McConnel J, Pecott J, Afify AM, Al-Khafaji B. Comparison of ThinPrep and TriPath PREP liquid-based preparations in nongynecologic specimens: a pilot study. Diagn Cytopathol. 2001;25:177–84.CrossRefGoogle Scholar
  37. 37.
    Nishino M, Wang HH. Should the thyroid AUS/FLUS category be further stratified by malignancy risk? Cancer Cytopathol. 2014;122:481–3. Scholar
  38. 38.
    Oertel YC. “Atypical” cells in fine-needle aspiration biopsy specimens of benign thyroid cysts. Cancer. 2006;108:72; author reply 73CrossRefGoogle Scholar
  39. 39.
    Padmanabhan V, Marshall CB, Akdas Barkan G, Ghofrani M, Laser A, Tolgay Ocal I, et al. Reproducibility of atypia of undetermined significance/follicular lesion of undetermined significance category using the Bethesda System for reporting thyroid cytology when reviewing slides from different institutions: a study of interobserver variability among cytopathologists. Diagn Cytopathol. 2017;45:399–405. Scholar
  40. 40.
    Persichetti A, Di Stasio E, Guglielmi R, Bizzarri G, Taccogna S, Misischi I, et al. Predictive value of malignancy of thyroid nodule ultrasound classification systems: a prospective study. J Clin Endocrinol Metab. 2018;103:1359–68. Scholar
  41. 41.
    Steward DL, Carty SE, Sippel RS, Yang SP, Sosa JA, Sipos JA, et al. Performance of a multigene genomic classifier in thyroid nodules with indeterminate cytology: a prospective blinded multicenter study. JAMA Oncol. 2018. [Epub ahead of print]; Scholar
  42. 42.
    Tripathy K, Mishra A, Singh AK, Panda PL, Mahapatra A, Lenka A. Immunocytochemistry using liquid-based cytology: a tool in hormone receptor analysis of breast cancer. J Cytol. 2018;35:260–4. Scholar
  43. 43.
    Tulecke MA, Wang HH. ThinPrep for cytologic evaluation of follicular thyroid lesions: correlation with histologic findings. Diagn Cytopathol. 2004;30:7–13.CrossRefGoogle Scholar
  44. 44.
    Valderrabano P, Khazai L, Thompson ZJ, Sharpe SC, Tarasova VD, Otto KJ, et al. Cancer risk associated with nuclear atypia in cytologically indeterminate thyroid nodules: a systematic review and meta-analysis. Thyroid. 2018;28:210–9. Scholar
  45. 45.
    Vivero M, Renshaw AA, Krane JF. Influence of descriptive terminology on management of atypical thyroid fine-needle aspirates. Cancer Cytopathol. 2014;122:175–81. Scholar
  46. 46.
    Wu HH, Inman A, Cramer HM. Subclassification of “atypia of undetermined significance” in thyroid fine-needle aspirates. Diagn Cytopathol. 2014;42:23–9. Scholar
  47. 47.
    Yang J, Schnadig V, Logrono R, Wasserman PG. Fine-needle aspiration of thyroid nodules: a study of 4703 patients with histologic and clinical correlations. Cancer. 2007;111:306–15.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.CBLPathRye BrookUSA
  2. 2.Department of Pathology and Laboratory MedicineNew York Presbyterian Hospital, Weill Cornell Medical CollegeNew YorkUSA

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