Molecular Diagnostics and [18F]FDG-PET/CT in Indeterminate Thyroid Nodules: Complementing Techniques or Waste of Valuable Resources?

Abstract

Background: An accurate preoperative workup of cytologically indeterminate thyroid nodules (ITN) may rule out malignancy and avoid diagnostic surgery for benign nodules. This study assessed the performance of molecular diagnostics (MD) and 2-[¹⁸F]fluoro-2-deoxy-d-glucose ([¹⁸F]FDG)-positron emission tomography/computed tomography (PET/CT) in ITN, including their combined use, and explored whether molecular alterations drive the differences in [¹⁸F]FDG uptake among benign nodules. Methods: Adult, euthyroid patients with a Bethesda III or IV thyroid nodule were prospectively included in this multicenter study. They all underwent MD and an [¹⁸F]FDG-PET/CT scan of the neck. MD was performed using custom next-generation sequencing panels for somatic mutations, gene fusions, and copy number alterations and loss of heterozygosity. Sensitivity, specificity, negative and positive predictive value (NPV, PPV), and benign call rate (BCR) were assessed for MD and [¹⁸F]FDG-PET/CT separately and for a combined approach using both techniques. Results: In 115 of the 132 (87%) included patients, MD yielded a diagnostic result on cytology. Sensitivity, specificity, NPV, PPV, and BCR were 80%, 69%, 91%, 48%, and 57% for MD, and 93%, 41%, 95%, 36%, and 32% for [¹⁸F]FDG-PET/CT, respectively. When combined, sensitivity and specificity were 95% and 44% for a double-negative test (i.e., negative MD plus negative [¹⁸F]FDG-PET/CT) and 68% and 86% for a double-positive test, respectively. Concordance was 63% (82/130) between MD and [¹⁸F]FDG-PET/CT. There were more MD-positive nodules among the [¹⁸F]FDG-positive benign nodules (25/59, 42%, including 11 (44%) isolated RAS mutations) than among the [¹⁸F]FDG-negative benign nodules (7/30, 19%, p = 0.02). In oncocytic ITN, the BCR of [¹⁸F]FDG-PET/CT was mere 3% and MD was the superior technique. Conclusions: MD and [¹⁸F]FDG-PET/CT are both accurate rule-out tests when unresected nodules that remain unchanged on ultrasound follow-up are considered benign. It may vary worldwide which test is considered most suitable, depending on local availability of diagnostics, expertise, and cost-effectiveness considerations. Although complementary, the benefits of their combined use may be confined when therapeutic consequences are considered, and should therefore not routinely be recommended. In nononcocytic ITN, sequential testing may be considered in case of a first-step MD negative test to confirm that withholding diagnostic surgery is oncologically safe. In oncocytic ITN, after further validation studies, MD might be considered. Clinical Trial Registration: This trial is registered with ClinicalTrials.gov: NCT02208544 (August 5, 2014), https://clinicaltrials.gov/ct2/show/NCT02208544.

Keywords: [18F]FDG-PET/CT; indeterminate cytology; molecular diagnostics; thyroid carcinoma; thyroid nodules.

FIG. 1.

Study flowchart. ^aCytological diagnosis on central review was FN. As the histopathological diagnosis was a oncocytic cell adenoma, full MD analysis was performed. ^bOf the 42 patients with oncocytic cytology, 10 had partially unsuccessful MD-based failed fusion and CNA-LOH analysis (n = 3) or failed fusion analysis (n = 7). As predefined, they were included in the statistical analysis as at least the somatic mutation analysis succeeded. ^cIn four patients with a driver mutation on CHS analysis (2 TERT, 1 PTEN, and 1 EGFR mutation), fusion analysis was performed to detect any additional driver mutations. [¹⁸F]FDG, 2-[¹⁸F]fluoro-2-deoxy-d-glucose; [¹⁸F]FDG-PET/CT, positron emission tomography/computed tomography using [¹⁸F]FDG; AUS, atypia of undetermined significance; CHS, cancer hotspot panel for somatic mutation analysis; CNA-LOH, copy number alterations and loss of heterozygosity; FN, follicular neoplasm; MD, molecular diagnostics; O-FN, oncocytic follicular neoplasm.

FIG. 2.

Preoperative diagnostic workup with stepwise use of MD and [¹⁸F]FDG-PET/CT. ^aAs visual [¹⁸F]FDG-PET/CT assessment does not differentiate in oncocytic nodules, it was not considered in this schematic representation of a preoperative diagnostic workup. ^bIncludes one case (case 84; Supplementary Table S5) in which MD was partially MD negative (somatic mutation analysis) and partially non-diagnostic (fusion and CNA-LOH analysis) on cytology. On histopathology, MD was positive based on a positive CNA-LOH analysis. ^cDiagnostic surgery or active surveillance may be considered; the decision may depend on other patient characteristics and patient preference (shared decision-making). ^dDiagnostic surgery or active surveillance may be considered; the decision may depend on the type of molecular alteration that is observed (also see Table 7 and Supplementary Table S5), and on other patient characteristics and patient preference (shared decision-making). +, test positive; −, test negative; ROM, rate of malignancy, defined as rate of malignancy or borderline tumor.