Diagnostic and prognostic value of a 7-panel mutation testing in thyroid nodules with indeterminate cytology: the SWEETMAC study

Stéphane Bardet, Nicolas Goardon, Justine Lequesne, Dominique Vaur, Renaud Ciappuccini, Alexandra Leconte, Hervé Monpeyssen, Virginie Saguet-Rysanek, Bénédicte Clarisse, Audrey Lasne-Cardon, Fabrice Ménégaux, Laurence Leenhardt, Camille Buffet, Stéphane Bardet, Nicolas Goardon, Justine Lequesne, Dominique Vaur, Renaud Ciappuccini, Alexandra Leconte, Hervé Monpeyssen, Virginie Saguet-Rysanek, Bénédicte Clarisse, Audrey Lasne-Cardon, Fabrice Ménégaux, Laurence Leenhardt, Camille Buffet

Abstract

Purpose: The aim of this prospective study (ClinicalTrials.gov: NCT01880203) was to evaluate the diagnostic and prognostic value of a 7-panel mutation testing in the aspirates of thyroid nodules with indeterminate cytology (IC).

Methods: Eligible patients had a thyroid nodule ≥15 mm with IC (Bethesda III-V) for which surgery had been recommended. Detection of BRAF and RAS mutations was performed using pyrosequencing and RET/PTC and PAX8/PPARγ rearrangements using Real-Time quantitative reverse transcription-polymerase chain reaction (RT-PCR).

Results: Among 131 nodules with IC, 21 (16%) were malignant including 20 differentiated cancers and one thyroid lymphoma. Molecular abnormalities were identified in 15 nodules with IC corresponding to 10 malignant and 5 benign tumours. BRAF mutation was detected in 4 nodules all corresponding to classic PTC, and PAX8/PPARγ rearrangement in 2 HCC. In contrast, RAS mutation was identified in eight nodules, of which four were malignant, and one RET/PTC3 rearrangement in a follicular adenoma. This data resulted in an accuracy of 88%, sensitivity of 48%, specificity of 95%, positive-predictive value of 67%, and negative-predictive value of 91%. After a 56 month's follow-up, the proportion of excellent response was similar in patients with molecular alterations (67%) and those without (60%).

Conclusions: By increasing the overall risk of cancer from 16 to 67% in mutated nodules and by diminishing it to 9% in wild-type, this study confirms the relevance of the 7-panel mutation testing in the diagnostic of nodules with IC. Genetic testing, however, did not predict outcome in the cancer patient subgroup.

Keywords: Diagnosis; Mutation; Prognosis; Thyroid cancer; Thyroid nodules.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Molecular alterations in patients with malignant or benign nodules for each cytological subgroup (Bethesda III, IV and V). WT wild-type, PTC papillary thyroid cancer, FVPTC papillary thyroid cancer with follicular variant, FTC follicular thyroid carcinoma, HCC Hürthle-cell carcinoma, PDTC poorly differentiated thyroid carcinoma
Fig. 2
Fig. 2
Test performances (a, sensitivity; b, specificity; c, PPV; d, NPV) according to cancer prevalence, PTC rate and BRAF positive PTC rate in previous studies (6, 12, 14–20) and in the present study. The quality of the linear model adjustment is displayed on each graph (R2 and p value)
Fig. 3
Fig. 3
Proposal for the use of 7-panel testing to guide clinical decision in patients with cytologically indeterminate nodules

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