Operative Management Versus Observation for Thyroid Nodules Larger than 4 cm with Benign Cytology

  • Nicole A. Cipriani
Part of the Difficult Decisions in Surgery: An Evidence-Based Approach book series (DDSURGERY)


Workup of thyroid nodules usually involves a multi-disciplinary approach, including fine needle aspiration (FNA) biopsy. The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) was devised to stratify patients into tiers with increasing risk for cancer, based on features identified on FNA. A number of studies have attempted to correlate thyroid nodule size with intrinsic risk of malignancy, as well as with false negative rates (nodules with a benign diagnosis on cytology but a malignant diagnosis on final surgical pathology following resection). The aims of this chapter are (1) to review studies that have evaluated the false negative rate of thyroid nodules based on size, (2) to summarize, analyze, and grade the published data, and (3) to make recommendations for treatment of large thyroid nodules.


Fine-needle aspiration (FNA) Ultrasonography Thyroid nodules False negative rates 


  1. 1.
    Cibas ES, Ali SZ. The Bethesda system for reporting thyroid cytopathology. Am J Clin Pathol. 2009;132(5):658–65.CrossRefPubMedGoogle Scholar
  2. 2.
    Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Cibas ES, Baloch ZW, Fellegara G, LiVolsi VA, Raab SS, Rosai J, Diggans J, Friedman L, Kennedy GC, Kloos RT, Lanman RB, Mandel SJ, Sindy N, Steward DL, Zeiger MA, Haugen BR, Alexander EK. A prospective assessment defining the limitations of thyroid nodule pathologic evaluation. Ann Intern Med. 2013;159(5):325–32.CrossRefPubMedGoogle Scholar
  4. 4.
    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(10):1121–31.CrossRefPubMedGoogle Scholar
  5. 5.
    Parikh PP, Allan BJ, Lew JI. Sex variability of fine-needle aspiration reliability in the diagnosis of malignancy in thyroid nodules ≥4 cm. Am J Surg. 2013;206(5):778–82.CrossRefPubMedGoogle Scholar
  6. 6.
    Albuja-Cruz MB, Goldfarb M, Gondek SS, Allan BJ, Lew JI. Reliability of fine-needle aspiration for thyroid nodules greater than or equal to 4 cm. J Surg Res. 2013;181(1):6–10.CrossRefPubMedGoogle Scholar
  7. 7.
    Kuru B, Gulcelik NE, Gulcelik MA, Dincer H. The false-negative rate of fine-needle aspiration cytology for diagnosing thyroid carcinoma in thyroid nodules. Langenbeck’s Arch Surg. 2010;395(2):127–32.CrossRefGoogle Scholar
  8. 8.
    Bohacek L, Milas M, Mitchell J, Siperstein A, Berber E. Diagnostic accuracy of surgeon-performed ultrasound-guided fine-needle aspiration of thyroid nodules. Ann Surg Oncol. 2012;19(1):45–51.CrossRefPubMedGoogle Scholar
  9. 9.
    Varshney R, Forest V-I, Zawawi F, Rochon L, Hier MP, Mlynarek A, Tamilia M, Payne RJ. Ultrasound-guided fine-needle aspiration of thyroid nodules: does size matter? Am J Otolaryngol. 2014;35(3):373–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Koo DH, Song K, Kwon H, Bae DS, Kim J-H, Min HS, Lee KE, Youn Y-K. Does tumor size influence the diagnostic accuracy of ultrasound-guided fine-needle aspiration cytology for thyroid nodules? Int J Endocrinol. 2016;2016(5):3803647–6.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Carrillo JF, Frias-Mendivil M, Ochoa-Carrillo FJ, Ibarra M. Accuracy of fine-needle aspiration biopsy of the thyroid combined with an evaluation of clinical and radiologic factors. Otolaryngol Head Neck Surg. 2000;122(6):917–21.CrossRefPubMedGoogle Scholar
  12. 12.
    Khalife S, Bouhabel S, Forest V-I, Hier MP, Rochon L, Tamilia M, Payne RJ. The McGill thyroid nodule Score’s (MTNS+) role in the investigation of thyroid nodules with benign ultrasound guided fine needle aspiration biopsies: a retrospective review. J Otolaryngol Head Neck Surg. 2016;45(1):29.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Raj MD, Grodski S, Woodruff S, Yeung M, Paul E, Serpell JW. Diagnostic lobectomy is not routinely required to exclude malignancy in thyroid nodules greater than four centimetres. ANZ J Surg. 2012;82(1–2):73–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Kulstad R. Do all thyroid nodules >4 cm need to be removed? An evaluation of thyroid fine-needle aspiration biopsy in large thyroid nodules. Endocr Pract. 2016;22(7):791–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Rosario PW, Salles DS, Bessa B. Low false-negative rate of cytology in thyroid nodules> 4 cm. Arq Bras Endocrinol Metabol. 2009;53(9):1143–5.CrossRefPubMedGoogle Scholar
  16. 16.
    Pinchot SN, Al-Wagih H, Schaefer S, Sippel R, Chen H. Accuracy of fine-needle aspiration biopsy for predicting neoplasm or carcinoma in thyroid nodules 4 cm or larger. Arch Surg. 2009;144(7):649–55.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Wharry LI, McCoy KL, Stang MT, Armstrong MJ, LeBeau SO, Tublin ME, Sholosh B, Silbermann A, Ohori NP, Nikiforov YE, Hodak SP, Carty SE, Yip L. Thyroid nodules (≥4 cm): can ultrasound and cytology reliably exclude cancer? World J Surg. 2014;38(3):614–21.CrossRefPubMedGoogle Scholar
  18. 18.
    McCoy KL, Jabbour N, Ogilvie JB, Ohori NP, Carty SE, Yim JH. The incidence of cancer and rate of false-negative cytology in thyroid nodules greater than or equal to 4 cm in size. Surgery. 2007;142(6):837–44. discussion 844.e1–3.CrossRefPubMedGoogle Scholar
  19. 19.
    Ucler R, Usluogulları CA, Tam AA, Ozdemir D, Balkan F, Yalcın S, Kıyak G, Ersoy PE, Guler G, Ersoy R, Cakır B. The diagnostic accuracy of ultrasound-guided fine-needle aspiration biopsy for thyroid nodules three centimeters or larger in size. Diagn Cytopathol. 2015;43(8):622–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Ucar AE, Sarikaya SM, Parlak Ö, Yalcin A. Effect of nodule size on the reliability of fine-needle aspiration biopsy in thyroid nodules. Turk J Med Sci. 2014;44(6):1002–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Mehanna R, Murphy M, McCarthy J, O’Leary G, Tuthill A, Murphy MS, Sheahan P. False negatives in thyroid cytology: impact of large nodule size and follicular variant of papillary carcinoma. Laryngoscope. 2013;123(5):1305–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Meko JB, Norton JA. Large cystic/solid thyroid nodules: a potential false-negative fine-needle aspiration. Surgery. 1995;118(6):996–1003. discussion 1003–4.CrossRefPubMedGoogle Scholar
  23. 23.
    Giles WH, Maclellan RA, Gawande AA, Ruan DT, Alexander EK, Moore FD, Cho NL. False negative cytology in large thyroid nodules. Ann Surg Oncol. 2015;22(1):152–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Porterfield JR, Grant CS, Dean DS, Thompson GB, Farley DR, Richards ML, Reading CC, Charboneau JW, Vollrath BK, Sebo TJ. Reliability of benign fine needle aspiration cytology of large thyroid nodules. Surgery. 2008;144(6):963–8. discussion 968–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Yoon JH, Kwak JY, Moon HJ, Kim MJ, Kim E-K. The diagnostic accuracy of ultrasound-guided fine-needle aspiration biopsy and the sonographic differences between benign and malignant thyroid nodules 3 cm or larger. Thyroid. 2011;21(9):993–1000.CrossRefPubMedGoogle Scholar
  26. 26.
    Ali SZ, Cibas E. The Bethesda system for reporting thyroid cytopathology: definitions, criteria and explanatory notes. New York: Springer; 2010. p. 23.CrossRefGoogle Scholar
  27. 27.
    Delellis RA, Lloyd RV, Heitz PU, Eng C, editors. World Health Organization classification of tumours. Lyon: IARC Press; 2004. p. 99.Google Scholar
  28. 28.
    Apel RL, Ezzat S, Bapat BV, Pan N, LiVolsi VA, Asa SL. Clonality of thyroid nodules in sporadic goiter. Diagn Mol Pathol. 1995;4(2):113–21.CrossRefPubMedGoogle Scholar
  29. 29.
    Daniels GH. What if many follicular variant papillary thyroid carcinomas are not malignant? A review of follicular variant papillary thyroid carcinoma and a proposal for a new classification. Endocr Pract. 2011;17(5):768–87.CrossRefPubMedGoogle Scholar
  30. 30.
    Cipriani NA, Nagar S, Kaplan SP, White MG, Antic T, Sadow PM, Aschebrook-Kilfoy B, Angelos P, Kaplan EL, Grogan RH. Follicular thyroid carcinoma: how have histologic diagnoses changed in the last half-century and what are the prognostic implications? Thyroid. 2015;25(11):1209–16.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Nikiforov YE, Seethala RR, Tallini G, Baloch ZW, Basolo F, Thompson LDR, Barletta JA, Wenig BM, Ghuzlan Al A, Kakudo K, Giordano TJ, Alves VA, Khanafshar E, Asa SL, El-Naggar AK, Gooding WE, Hodak SP, Lloyd RV, Maytal G, Mete O, Nikiforova MN, Nosé V, Papotti M, Poller DN, Sadow PM, Tischler AS, Tuttle RM, Wall KB, LiVolsi VA, Randolph GW, Ghossein RA. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2016;2(8):1023–9.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Strickland KC, Howitt BE, Marqusee E, Alexander EK, Cibas ES, Krane JF, Barletta JA. The impact of noninvasive follicular variant of papillary thyroid carcinoma on rates of malignancy for fine-needle aspiration diagnostic categories. Thyroid. 2015;25(9):987–92.CrossRefPubMedGoogle Scholar
  33. 33.
    Faquin WC, Wong LQ, Afrogheh AH, Ali SZ, Bishop JA, Bongiovanni M, Pusztaszeri MP, VandenBussche CJ, Gourmaud J, Vaickus LJ, Baloch ZW. 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(3):181–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Can AS, Peker K. Comparison of palpation-versus ultrasound-guided fine-needle aspiration biopsies in the evaluation of thyroid nodules. BMC Res Notes. 2008;1:12.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Wu M. A comparative study of 200 head and neck FNAs performed by a cytopathologist with versus without ultrasound guidance: evidence for improved diagnostic value with ultrasound guidance. Diagn Cytopathol. 2011;39(10):743–51.CrossRefPubMedGoogle Scholar
  36. 36.
    Cavallo A, Johnson DN, White MG, Siddiqui S, Antic T, Mathew M, Grogan RH, Angelos P, Kaplan EL, Cipriani NA. Thyroid nodule size at ultrasound as a predictor of malignancy and final pathologic size. Thyroid. 2017;27(5):641–50.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.The University of Chicago, Department of PathologyChicagoUSA

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