The thyroid risk score (TRS) for nodules with indeterminate cytology

in Endocrine-Related Cancer
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  • 1 Division of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy
  • 2 Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
  • 3 Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Milan, Italy
  • 4 Pathology Unit, Istituto Auxologico Italiano IRCCS, Milan, Italy
  • 5 Endocrine Surgery Unit, Istituto Auxologico Italiano IRCCS, Milan, Italy
  • 6 Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy

Correspondence should be addressed to L Fugazzola: laura.fugazzola@unimi.it

*(C Colombo and M Muzza contributed equally to this work)

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Cytology is the gold standard method for the differential diagnosis of thyroid nodules, though 25–30% of them are classified as indeterminate. We aimed to set up a ‘thyroid risk score’ (TRS) to increase the diagnostic accuracy in these cases. We prospectively tested 135 indeterminate thyroid nodules. The pre-surgical TRS derived from the sum of the scores assigned at cytology, EU-TIRADS classification, nodule measurement, and molecular characterization, which was done by our PTC-MA assay, a customized array able to cost-effectively evaluate 24 different genetic alterations including point mutations and gene fusions. The risk of malignancy (ROM) increased paralleling the score: in the category >4 and ≤ 6 (low suspicion), >6 ≤ 8 (intermediate suspicion), and >8 (high suspicion); ROM was 10, 47 and 100%, respectively. ROC curves selected the score >6.5 as the best threshold to differentiate between malignant and benign nodules (P < 0.001). The TRS > 6.5 had a better performance than the single parameters evaluated separately, with an accuracy of 77 and 82% upon inclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features among malignant or benign cases, respectively. In conclusion, for the first time, we generated a score combining a cost-effective molecular assay with already validated tools, harboring different specificities and sensitivities, for the differential diagnosis of indeterminate nodules. The combination of different parameters reduced the number of false negatives inherent to each classification system. The TRS > 6.5 was highly suggestive for malignancy and retained a high accuracy in the identification of patients to be submitted to surgery.

Supplementary Materials

    • Supplementary Table 1: Molecular alterations detected in fine-needle aspiration samples and associated cancer risk (ROM, Risk of Malignancy). Values in square brackets indicate data considering NIFTPs as benign.
    • Supplementary Figure 1: In the 2.5 years period here considered (September 2017 to February 2020), 2215 cytological examinations were carried out at our Institution. The 138 nodules with indeterminate cytology (Bethesda III and IV) were submitted to genetic analyses and 65 of them underwent surgery.
    • Supplementary Figure 2: quality evaluation of fine needle aspirates before genetic analysis. To test the follicular content of the samples, PAX8 expression was evaluated on cDNA by both semiquantitative RT-PCR (upper panel) and PTC-MA assay analyses (lower panel).
    • Supplementary Figure 3: Hematoxylin-Eosin staining of #52 sample, a follicular adenoma with solid pattern and oxyphilous cell component (upper panel) harboring a double NRASQ61R + TERTG228A mutation (lower panel). A) Histological specimen showing the macroscopic features of a round, well-defined nodule surrounded by a fibrous capsule (B, C-hematoxylin-eosin staining-5X magnification). The same specimen at higher magnification (D-10X and E-40X).

 

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