474 chapter 12 mutation analysis was performed first; when this yielded no (likely) pathogenic driver alterations (i.e., no IARC classification system class 4 or 5, respectively), gene fusion analysis was additionally performed [687]. All three NGS panels were simultaneously performed in nodules with oncocytic cells on cytology. At the discretion of the dedicated thyroid pathologist who performed a blinded review of the cytology smears to select those with the highest cellularity for MD, this included cytology suspicious for a oncocytic follicular neoplasm (O-FN) as well as cytology with atypia of undetermined significance (AUS) with suspicion of oncocytic cells [27]. When any of the NGS panels yielded a nondiagnostic result due to quantity and/or quality issues with of the cytology sample, they were repeated on formalin-fixed paraffin-embedded (FFPE) surgical histopathology samples using FFPE tissue cores (0.6 mm diameter and variable length). MD was considered successful on cytology when at least the somatic mutation analysis succeeded. A positive MD result was defined as any (likely) pathogenic alteration (i.e., IARC class 4 or 5, respectively) or gene fusion, and/or any suspicious genome haploidization (GH) type CNA, defined as an uncertain malignant or malignant GH type CNA pattern as previously described (Chapter 11 of this thesis, figure 2)[687, 695]. Reference standard The reference standard was histopathology or active surveillance in case thyroid surgery was not performed. Per trial protocol, follow-up was at least one year after the [18F]FDG-PET/CT. Follow-up data were updated until 01 May 2023. Histopathology was centrally reviewed by a dedicated thyroid pathologist in accordance with the WHO classification (5th edition) after completion of trial procedures [22]. In case of a discordant review, a second dedicated pathologist was consulted for a consensus meeting. Pathologists were blinded for cytology, MD, and [18F]FDG-PET/CT results. The reference standard was considered positive when histopathology yielded a malignancy or a borderline tumour, including non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) or follicular tumour of uncertain malignant potential (FT-UMP), as diagnostic thyroid surgery is considered justified for these borderline diagnoses [19, 22]. Incidentally detected (micro)carcinomas located outside the index nodule were not considered. For patients undergoing active surveillance, including patients with positive test results (i.e., MD positive and/or [18F]FDG positive), the nodule was presumed benign when it remained unchanged on ultrasound follow-up (i.e., false-positive in case of a positive index test). Statistical analysis Mean ± standard deviation or median and interquartile range, and absolute numbers and relative frequencies (%) were used as descriptive statistics for continuous and categorical variables, respectively. Categorical outcomes were compared using Pearson’s chi-squared or Fisher’s exact tests, where appropriate. Nonparametric continuous variables were compared using the Mann-
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