, Volume 63, Issue 3, pp 430–438 | Cite as

Italian consensus for the classification and reporting of thyroid cytology: the risk of malignancy between indeterminate lesions at low or high risk. A systematic review and meta-analysis

  • Pierpaolo TrimboliEmail author
  • Anna Crescenzi
  • Marco Castellana
  • Francesco Giorgino
  • Luca Giovanella
  • Massimo Bongiovanni



Italian consensus for the classification and reporting of thyroid cytology has proposed to discriminate the cancer prevalence of high (Tir 3B) vs. low (Tir 3A) risk indeterminate nodules. To obtain more robust evidence on this topic, we performed a meta-analysis of the Odds Ratio (OR) of malignancy of Tir 3B vs. Tir 3A nodules.


A comprehensive literature exploration of online databases was conducted until May 2018. Original articles reporting histology of nodules cytologically classified as Tir 3A and Tir 3B were eligible. Pooled cancer prevalence in Tir 3A and Tir 3B, and OR of Tir 3B vs. Tir 3A were calculated.


The search revealed 95 articles, and 10 were included for the meta-analysis. Overall, 1168 indeterminate lesions were reported (441 Tir 3A and 727 Tir 3B), of which 391 were cancers. The pooled cancer prevalence was 17% in Tir 3A and 47% in Tir 3B. The OR of Tir 3B vs. Tir 3A was 4.24 (95% CI 2.75 to 6.53) with mild heterogeneity and without publication bias. When we considered non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) as non-malignant, cancer rate was lower, and OR of Tir 3B against Tir 3A was 2.93 (95% CI 1.60 to 5.37), with no heterogeneity but with publication bias.


The Italian system for thyroid cytology is reliable to assess indeterminate lesions at low and high risk, being Tir 3B associated with a cancer risk significantly higher than Tir 3A, also when considering NIFTP as non-malignant entity.


Fine-needle aspiration (FNA) Indeterminate nodules Thyroid Carcinoma Risk of malignancy 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

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  1. 1.
    H. Gharib, E. Papini, R. Paschke et al. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules. Endocr. Pract. 16(Suppl 1), 1–43 (2010)CrossRefPubMedGoogle Scholar
  2. 2.
    B.R. Haugen, E.K. Alexander, K.C. Bible 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 26, 1–133 (2016)CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Z.W. Baloch, S. Fleisher, V.A. LiVolsi, P.K. Gupta, Diagnosis of “follicular neoplasm”: a gray zone in thyroid fine-needle aspiration cytology. Diagn. Cytopathol. 26, 41–44 (2002)CrossRefPubMedGoogle Scholar
  4. 4.
    E.K. Alexander, G.C. Kennedy, Z.W. Baloch et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N. Engl. J. Med. 367, 705–715 (2012)CrossRefPubMedGoogle Scholar
  5. 5.
    P. Perros, K. Boelaert, S. Colley et al. Guidelines for the management of thyroid cancer. Clin. Endocrinol. 81(Suppl 1), 1–122 (2014)CrossRefGoogle Scholar
  6. 6.
    E.S. Cibas, S.Z. Ali, The Bethesda system for reporting thyroid cytopathology. Thyroid 19, 1159–1165 (2009)CrossRefPubMedGoogle Scholar
  7. 7.
    F. Nardi, F. Basolo, A. Crescenzi et al. Italian consensus for the classification and reporting of thyroid cytology. J. Endocrinol. Invest. 37, 593–599 (2014)CrossRefPubMedGoogle Scholar
  8. 8.
    P. Trimboli, A. Crescenzi, L. Giovanella, Performance of Italian Consensus for the Classification and Reporting of Thyroid Cytology (ICCRTC) in discriminating indeterminate lesions at low and high risk of malignancy. A systematic review and meta-analysis. Endocrine 60, 31–35 (2018)CrossRefPubMedGoogle Scholar
  9. 9.
    Y.E. Nikiforov, R.A. Ghossein, K. Kakudo et al. in Non-invasive follicular thyroid neoplasm with papillary-like nuclear features. World Health Organization Classification of Tumours of Endocrine Organs. ed. by R.V. Lloyd, R.Y. Osamura, G. Kloppel, J. Rosai. (IARC, Lyon, France, 2017) pp. 78–80Google Scholar
  10. 10.
    R. DerSimonian, N. Laird, Meta-analysis in clinical trials. Control. Clin. Trials 7, 177–188 (1986)CrossRefPubMedGoogle Scholar
  11. 11.
    F. Song, Exploring heterogeneity in meta-analysis: Is the L’Abbé plot useful? J. Clin. Epidemiol. 52, 725–730 (1999)CrossRefPubMedGoogle Scholar
  12. 12.
    K.A. L’Abbé, A.S. Detsky, K. O’Rourke, Meta-analysis in clinical research. Ann. Intern. Med. 107, 224–233 (1987)CrossRefPubMedGoogle Scholar
  13. 13.
    P. Trimboli, L. Guidobaldi, S. Amendola et al. Galectin-3 and HBME-1 improve the accuracy of core biopsy in indeterminate thyroid nodules. Endocrine 52, 39–45 (2016)CrossRefPubMedGoogle Scholar
  14. 14.
    F. Tartaglia, A. Giuliani, L. Tromba et al. Fine needle aspiration cytology of 650 thyroid nodules operated for multinodular goiter: a cyto-histological correlation based on the new Italian cytological classification (SIAPEC 2014). J. Biol. Regul. Homeost. Agents 30, 1187–1193 (2016)PubMedGoogle Scholar
  15. 15.
    G. Grani, L. Lamartina, V. Ascoli et al. Ultrasonography scoring systems can rule out malignancy in cytologically indeterminate thyroid nodules. Endocrine 57, 256–261 (2017)CrossRefPubMedGoogle Scholar
  16. 16.
    F. Quaglino, V. Marchese, E. Mazza, C. Gottero, R. Lemini, S. Taraglio, When is thyroidectomy the right choice? Comparison between fine-needle aspiration and final histology in a single institution experience. Eur. Thyroid J. 6, 94–100 (2017)CrossRefPubMedGoogle Scholar
  17. 17.
    S. Ulisse, D. Bosco, F. Nardi et al. Thyroid imaging reporting and data system score combined with the new italian classification for thyroid cytology improves the clinical management of indeterminate nodules. Int. J. Endocrinol. 2017, 9692304 (2017)CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    F. Medas, E. Erdas, L. Gordini et al. Risk of malignancy in thyroid nodules classified as TIR-3A: what therapy? Int. J. Surg. 41(Suppl 1), S60–S64 (2017)CrossRefPubMedGoogle Scholar
  19. 19.
    P. Straccia, A. Santoro, E.D. Rossi et al. Incidence, malignancy rates of diagnoses and cyto-histological correlations in the new Italian Reporting System for Thyroid Cytology: an institutional experience. Cytopathology 28, 503–508 (2017)CrossRefPubMedGoogle Scholar
  20. 20.
    E. Rullo, G. Minelli, D. Bosco, F. Nardi, V. Ascoli, Evaluation of the Italian cytological subclassification of thyroid indeterminate nodules into TIR-3A and TIR-3B: a retrospective study of 290 cases with histological correlation from a single institution. J. Endocrinol. Invest. 41, 531–538 (2018)CrossRefPubMedGoogle Scholar
  21. 21.
    P. Trimboli, F. Fulciniti, E. Merlo, J. Barizzi, L. Mazzucchelli, L. Giovanella, Histologic outcome of indeterminate thyroid nodules classified at low or high risk. Endocr. Pathol. 29, 75–79 (2018)CrossRefPubMedGoogle Scholar
  22. 22.
    C. Sparano, G. Parenti, A. Cilotti et al. Clinical impact of the new SIAPEC-IAP classification on the indeterminate category of thyroid nodules. J. Endocrinol. Invest. (2018).
  23. 23.
    A. Lauria, E. Maddaloni, S.I. Briganti 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. 178, 595–603 (2018)CrossRefGoogle Scholar
  24. 24.
    P. Straccia, E.D. Rossi, T. Bizzarro et al. A meta-analytic review of the Bethesda system for reporting thyroid cytopathology: has the rate of malignancy in indeterminate lesions been underestimated? Cancer Cytopathol. 123, 713–722 (2015)CrossRefPubMedGoogle Scholar
  25. 25.
    M. Bongiovanni, A. Spitale, W.C. Faquin, L. Mazzucchelli, Z.W. Baloch, The Bethesda system for reporting thyroid cytopathology: a meta-analysis. Acta Cytol. 56, 333–339 (2012)CrossRefPubMedGoogle Scholar
  26. 26.
    S.H. Ahn, S.D. Kim, W.J. Jeong, Comparison of risk of malignancy in a subgroup with atypia of undetermined significance/follicular lesion of undetermined significance: a meta-analysis. Head Neck 39, 1699–1710 (2017)CrossRefPubMedGoogle Scholar
  27. 27.
    P. Valderrabano, L. Khazai, Z.J. Thompson, S.C. Sharpe, V.D. Tarasova, K.J. Otto, J.E. Hallanger-Johnson, J.T. Wadsworth, B.M. Wenig, C.H. Chung, B.A. Centeno, B. McIver, Cancer risk associated with nuclear atypia in cytologically indeterminate thyroid nodules: a systematic review and meta-analysis. Thyroid 28, 210–219 (2018)CrossRefPubMedGoogle Scholar
  28. 28.
    S.Z. Ali, E. Cibas. The Bethesda System for Reporting Thyroid Cytopathology, 2nd edn. (Springer, Cham, Switzerland, 2017)Google Scholar
  29. 29.
    M. Pusztaszeri, E.D. Rossi, M. Auger, Z. Baloch, J. Bishop, M. Bongiovanni, A. Chandra, B. Cochand-Priollet, G. Fadda, M. Hirokawa, S. Hong, K. Kakudo, J.F. Krane, R. Nayar, S. Parangi, F. Schmitt, W.C. Faquin, The Bethesda system for reporting thyroid cytopathology: proposed modifications and updates for the second edition from an international panel. Acta Cytol. 60, 399–405 (2016)CrossRefPubMedGoogle Scholar
  30. 30.
    C. Bellevicine, R. Sgariglia, I. Migliatico et al. Different qualifiers of AUS/FLUS thyroid FNA have distinct BRAF, RAS, RET/PTC, and PAX8/PPARg alterations. Cancer Cytopathol. 126, 317–325 (2018)CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Nuclear Medicine and Thyroid CentreOncology Institute of Southern SwitzerlandBellinzonaSwitzerland
  2. 2.Section of PathologyUniversity Hospital Campus Bio MedicoRomeItaly
  3. 3.Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic DiseasesUniversity of Bari Aldo MoroBariItaly
  4. 4.Service of Clinical Pathology, Institute of PathologyLausanne University HospitalLausanneSwitzerland

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