Developing a tool that could reliably refute total thyroidectomy for solitary Bethesda IV thyroid nodules



To assess the reliability of a simple, accessible, cost-effective rule-out tool, for use in triaging patients with Bethesda IV nodules to appropriate surgery.


The diagnostic tool was assembled by combining the negativity for suspicious ultrasound features (irregular margins, microcalcification, and a taller-than-wide orientation), and mutational marker negativity (BRAF and NRAS). The tool, (US/mutation), was tested on 167 patients with solitary Bethesda IV nodules. The primary outcome was its negative predictive value (NPV) for lesions requiring total thyroidectomy (TT). The impact of mutational marker negativity, as part of the tool, was evaluated by comparing the NPV of (US/mutation) to that of (US/mutation+).


10 out of 167 lesions were positive for a mutational marker. These underwent TT, and only 2/10 (20%) were benign, on final histology. In 6/8 malignant lesions, TT was concordant with current clinical guidelines. 157 patients comprised the negative study cohort, for both mutational markers and suspicious US features. These underwent thyroid lobectomy, and 17 cases resulted in malignancy, only 8 of which required completion thyroidectomy. Accordingly, the NPV of (US/mutation) for malignancy was 89% (140/157), and 95% (149/157) for malignancy requiring TT. However, the NPV of (US/mutation+) was 20% for malignancy, and 40% for malignancy requiring TT. These differences were statistically significant (89% vs. 20%; p < 0.0001, and 95% vs. 40%; p < 0.0001).


US/mutation is a reliable rule-out tool, with sufficient diagnostic accuracy to spare patients, with Bethesda IV nodules, an overly radical TT.

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Data availability

The data supporting the findings of this study are available from the corresponding author, upon request.


  1. 1.

    Nikiforov YE, Yip L, Nikiforova MN (2013) New strategies in diagnosing cancer in thyroid nodules: impact of molecular markers. Clin Cancer Res 19:2283–2288

    CAS  Article  Google Scholar 

  2. 2.

    Miccoli P, Bakkar S (2017) Surgical management of papillary thyroid carcinoma: an overview. Updates Surg 69:145–150

    Article  Google Scholar 

  3. 3.

    De Napoli L, Bakkar S, Ambrosini CE et al (2016) Indeterminate single thyroid nodule: synergistic impact of mutational markers and sonographic features in triaging patients to appropriate surgery. Thyroid 26:390–394

    Article  Google Scholar 

  4. 4.

    Remonti LR, Kramer CK, Leitão CB et al (2015) Thyroid ultrasound features and risk of carcinoma: a systematic review and meta-analysis of observational studies. Thyroid 25:538–550

    Article  Google Scholar 

  5. 5.

    Haugen BR, Alexander EK, Bible KC et al (2016) 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid 26:1–133

    Article  Google Scholar 

  6. 6.

    Bakkar S, Materazzi G, Biricotti M et al (2016) Minimally invasive video-assisted thyroidectomy (MIVAT)from A to Z. Surg Today 46:255–259

    Article  Google Scholar 

  7. 7.

    Materazzi G, Fregoli L, Papini P et al (2018) Robot-assisted transaxillary thyroidectomy (RATT): a series appraisal of more than 250 cases from Europe. World J Surg 42:1018–1023

    Article  Google Scholar 

  8. 8.

    Miccoli P, Fregoli L, Rossi L et al (2020) Minimally invasive video-assisted thyroidectomy (MIVAT). Gland Surg 9:S1–S5

    Article  Google Scholar 

  9. 9.

    Campbell I (2007) Chi-squared and Fisher-Irwin tests of two-by-two tables with small sample recommendations. Stat Med 26:3661–3675

    Article  Google Scholar 

  10. 10.

    Richardson JT (2011) The analysis of 2 × 2 contingency tables—yet again. Stat Med 30:890 (author reply 891-892)

    Article  Google Scholar 

  11. 11.

    Altman DG, Machin D, Bryant TN, Gardner MJ (eds) (2000) Statistics with confidence, 2nd edn. BMJ Books, London

    Google Scholar 

  12. 12.

    Frates MC, Benson CB, Doubilet PM et al (2006) Prevalence and distribution of carcinoma in patients with solitary and multiple thyroid nodules on sonography. J Clin Endocrinol Metab 91:3411–3417

    CAS  Article  Google Scholar 

  13. 13.

    Andrioli M, Carzaniga C, Persani L (2013) Standardized ultrasound report for thyroid nodules: The Endocrinologist’s viewpoint. Eur Thyroid J 2:37–48

    Article  Google Scholar 

  14. 14.

    Tessler FN, Middleton WD, Grant EG et al (2017) Thyroid imaging, reporting and data system (TI-RADS): white paper of the ACR TI-RADS committee. J Am Coll Radiol 14:587–595

    Article  Google Scholar 

  15. 15.

    Bojunga J, Herrmann E, Meyer G et al (2010) Real-time elastography for the differentiation of benign and malignant thyroid nodules: a meta-analysis. Thyroid 20:1145–1150

    Article  Google Scholar 

  16. 16.

    Ohori NP, Wolfe J, Hodak SP et al (2013) “Colloid-rich” follicular neoplasm/ suspicious for follicular neoplasm thyroid fine needle aspiration specimens: cytologic, histologic, and molecular basis for considering an alternate view. Cancer Cytopathol 121:718–728

    Article  Google Scholar 

  17. 17.

    Bakkar S, Macerola E, Aljarrah Q et al (2019) BRAF(V600E) mutation: a potential predictor of more than a Sistrunk's procedure in patients with thyroglossal duct cyst carcinoma and a normal thyroid gland. Updates Surg.

    Article  PubMed  Google Scholar 

  18. 18.

    Parangi S, Suh H (2014) The role of genetic markers in the evaluation and management of thyroid nodules. Surg Clin N Am 94:515–528

    Article  Google Scholar 

  19. 19.

    Yip L (2015) Molecular markers for thyroid cancer diagnosis, prognosis, and targeted therapy. J Surg Oncol 111:43–50

    CAS  Article  Google Scholar 

  20. 20.

    Macerola E, Torregrossa L, Ugolini C et al (2017) BRAFK601E Mutation in a Follicular Thyroid Adenoma: A Case Report. Int J Surg Pathol 25:348–351

    Article  Google Scholar 

  21. 21.

    Capelli L, Marfisi C, Puccetti M et al (2015) Role of BRAF molecular analysis in the management of papillary thyroid carcinoma: analysis of cytological and histological samples. Cytopathology 26:297–301

    CAS  Article  Google Scholar 

  22. 22.

    Cibas ES, Ali SZ (2009) The Bethesda System for Reporting Thyroid Cytopathology. Thyroid 19:1159–1165

    Article  Google Scholar 

  23. 23.

    World Health Organization (2004) Pathology and genetics of tumor of endocrine organs. World Health Organization classification of tumors. IARC Press, Lyon

    Google Scholar 

  24. 24.

    Bakkar S, Macerola E, Aljarrah Q et al (2019) BRAF V600E mutation: a potential predictor of more than a Sistrunk's procedure in patients with thyroglossal duct cyst carcinoma and a normal thyroid gland. Updates Surg. of print)

    Article  PubMed  Google Scholar 

  25. 25.

    Macerola E, Rago T, Proietti A et al (2019) The mutational analysis in the diagnostic work-up of thyroid nodules: the real impact in a center with large experience in thyroid cytopathology. J Endocrinol Invest 42:157–166

    CAS  Article  Google Scholar 

  26. 26.

    Morris LG, Myssiorek D (2010) Improved detection does not fully explain the rising incidence of well-differentiated thyroid cancer: a population-based analysis. Am J Surg 200:454–461

    Article  Google Scholar 

  27. 27.

    Camargo RYA, Tomimori EK, Knobel M et al (2007) Pre-operative assessment of thyroid nodules: respective roles of ultra-sonography, fine needle aspiration biopsy followed by cytology. Clinics 62:411–418

    Article  Google Scholar 

  28. 28.

    Cibas ES, Ali SZ (2017) The 2017 Bethesda system for reporting thyroid cytopathology. Thyroid 27:1341–1346

    Article  Google Scholar 

  29. 29.

    Seshadri KG (2017) A pragmatic approach to the indeterminate thyroid nodule. Indian J Endocr Metab 21:751–757

    Article  Google Scholar 

  30. 30.

    de Koster EJ, de Geus-Oei LF, Dekkers OM et al (2018) Diagnostic utility of molecular and imaging biomarkers in cytological indeterminate thyroid nodules. Endocr Rev 39:154–191

    Article  Google Scholar 

  31. 31.

    Kwak JY, Han KH, Yoon JH et al (2011) Thyroid imaging reporting and data system for US features of nodules: a step in establishing better stratification of cancer risk. Radiology 260:892–899

    Article  Google Scholar 

  32. 32.

    Chng CL, Tan HC, Too CW et al (2018) Diagnostic performance of ATA, BTA and TIRADS sonographic patterns in the predication of malignancy in histologically proven thyroid nodules. Singapore Med J 59:578–583

    Article  Google Scholar 

  33. 33.

    Jeh SK, Jung SL, Kim BS, Lee YS (2007) Evaluating the degree of conformity of papillary carcinoma and follicular carcinoma to the reported ultrasonographic findings of malignant thyroid tumor. Korean J Radiol 8:192–197

    Article  Google Scholar 

  34. 34.

    Lee SH, Baek JS, Lee JY et al (2013) Predictive factors of malignancy in thyroid nodules with a cytological diagnosis of follicular neoplasm. Endocr Pathol 24:177–183

    Article  Google Scholar 

  35. 35.

    Chaigneau E, Russ G, Royer B et al (2018) TIRADS score is of limited clinical value for risk stratification of indeterminate cytological results. Eur J Endocrinol 179:13–20

    CAS  Article  Google Scholar 

  36. 36.

    Nishino M, Nikiforova M (2018) Update on Molecular Testing for Cytologically Indeterminate Thyroid Nodules. Arch Pathol Lab Med 14:446–457

    Article  Google Scholar 

  37. 37.

    Bakkar S, Papavramidis TS, Aljarrah Q et al (2020) Energy-based devices in thyroid surgery—an overview. Gland Surg 9(Supp 1):S14–S17.

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Fundakowski CE, Hales NW, Agrawal N et al (2018) Surgical management of the recurrent laryngeal nerve in thyroidectomy: American Head and Neck Society Consensus Statement. Head Neck 40:663–675

    Article  Google Scholar 

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This study was not funded by any grant.

Author information




Corresponding author SB: study concept and design, data interpretation, article writing, final approval, accountability for all aspects of the work. EM and AP: data collection and interpretation, final approval, accountability for all aspects of the work. QA, KA, GM, FB, PM: critical revision, final approval, accountability for all aspects of the work.

Corresponding author

Correspondence to Sohail Bakkar.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Bakkar, S., Macerola, E., Proietti, A. et al. Developing a tool that could reliably refute total thyroidectomy for solitary Bethesda IV thyroid nodules. Updates Surg 73, 281–288 (2021).

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  • Indeterminate thyroid nodule
  • Bethesda IV
  • Thyroid cancer
  • Extent of thyroid surgery