, Volume 57, Issue 1, pp 98–107 | Cite as

Proposal for a novel management of indeterminate thyroid nodules on the basis of cytopathological subclasses

  • Martina Rossi
  • Sabrina Lupo
  • Roberta Rossi
  • Paola Franceschetti
  • Giorgio Trasforini
  • Stefania Bruni
  • Federico Tagliati
  • Mattia Buratto
  • Giovanni Lanza
  • Luca Damiani
  • Ettore degli Uberti
  • Maria Chiara ZatelliEmail author
Original Article


Indeterminate thyroid nodules include heterogeneous lesions that could benefit from a differential management. Our aim is to better define the management of the Bethesda System for Reporting Thyroid Cytopathology class III and IV nodules, by identifying cytological subcategories among Bethesda System for Reporting Thyroid Cytopathology class III associated with different clinical risk, by means of ultrasound, repeated FNAB, and BRAFV600E molecular analysis. We also evaluated the outcome of nodules not operated, over a 5-year follow-up. Out of 460 nodules (269 Bethesda System for Reporting Thyroid Cytopathology class III and 191 Bethesda System for Reporting Thyroid Cytopathology class IV), 344 were operated on surgical group and 116 followed-up conservatively (follow-up group). Bethesda System for Reporting Thyroid Cytopathology class III was divided into four subcategories on the basis of cytomorphological features (III-1, III-2, III-3, III-4). Clinical risk was defined on the basis of histological, cytological, and ultrasound data. Malignancy was higher in Bethesda System for Reporting Thyroid Cytopathology class III vs. Bethesda System for Reporting Thyroid Cytopathology class IV (34.4 vs. 26.2 %; p < 0.01). Papillary thyroid carcinoma was the most frequent cancer in each Bethesda System for Reporting Thyroid Cytopathology class (35 %). BRAFV600E diagnostic accuracy was 87 %. Repeated FNAB reclassified as benign nearly 40 % of nodules, selecting patients where surgery could be spared. Significant nodule growth occurred in 13.7 % of nodules, belonging mostly to Bethesda System for Reporting Thyroid Cytopathology class III-2 and Bethesda System for Reporting Thyroid Cytopathology class IV. Overall clinical risk was higher in Bethesda System for Reporting Thyroid Cytopathology III-1, III-4, and IV classes. We propose a differential management of Bethesda System for Reporting Thyroid Cytopathology III and IV classes and related subcategories: surgery may be indicated in Bethesda System for Reporting Thyroid Cytopathology class III-1, III-4, and IV; a conservative follow-up avoiding repeated FNAB may be appropriated in class III-3, while repeated FNAB may be useful in class III-2.


Thyroid nodule management Indeterminate thyroid nodule Cytological sub-categories Thyroid nodule clinical risk 



This work was supported by grants from the Italian Ministry of Education, Research and University (FIRB RBAP11884 M, RBAP1153LS), Associazione Italiana per la Ricerca sul Cancro (AIRC) in collaboration with “Laboratorio in rete del Tecnopolo Tecnologie delle terapie avanzate” (LTTA) of the University of Ferrara.

Compliance with ethical standards

Conflict of interest

MCZ has received consultant fees from Novartis and Genzyme. EdU has received consultant fees from Novartis and grant support from Sanofi. The remaining authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Martina Rossi
    • 1
    • 2
  • Sabrina Lupo
    • 1
  • Roberta Rossi
    • 2
  • Paola Franceschetti
    • 2
  • Giorgio Trasforini
    • 2
  • Stefania Bruni
    • 2
  • Federico Tagliati
    • 1
    • 2
  • Mattia Buratto
    • 1
  • Giovanni Lanza
    • 3
  • Luca Damiani
    • 1
  • Ettore degli Uberti
    • 1
    • 2
  • Maria Chiara Zatelli
    • 1
    • 2
    Email author
  1. 1.Section of Endocrinology & Internal Medicine, Department of Medical SciencesUniversity of FerraraFerraraItaly
  2. 2.Endocrinology UnitAzienda Ospedaliero-Universitaria di FerraraFerraraItaly
  3. 3.Section of Pathology and Biomolecular Diagnostics, Department of Morphology, Surgery and Experimental MedicineUniversity of FerraraFerraraItaly

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