General discussion 505 13 inversely related to prognosis in differentiated thyroid carcinoma [498, 499]. In the EfFECTS trial, two false-negative nodules were reported. During the blinded histopathological assessment, both cases were among the top 10% most difficult cases to diagnose. The two nodules were only classified as malignant after extensive assessments including molecular analysis by multiple expert thyroid pathologists, including revision of the histopathology by a pathologist from the University of Pittsburgh Medical Centre (Pittsburgh, PA, USA) for one of the two nodules. As described in more detail in the supplementary data corresponding to Chapter 4 of this thesis, the first nodule was a 15-mm non-invasive neoplasm with uncommon spindle cell metaplasia and a RAS mutation, which was ultimately classified as a papillary thyroid carcinoma (TNM pT1b), considering follicular adenoma in the differential diagnosis. In the results of our studies, we have not been able to uncover a plausible explanation for this nodules’ false-negativity on [18F]FDG-PET/CT. As presented in Chapter 12 of this thesis, all other nodules carrying RAS mutations in our study cohort were [18F]FDG positive [725]. Later on in this discussion, the possible correlation between molecular alterations and the uptake of [18F]FDG is conferred. The second [18F]FDG false negative nodule was a 32-mm predominantly cystic, non-invasive neoplasm with a solid component of 8 mm. With a differential diagnosis of well differentiated tumour of uncertain malignant potential (WDT-UMP) or non-invasive follicular neoplasm with papillary-like nuclear features (NIFTP), the nodule was only considered malignant (follicular variant of PTC, TNM pT2) after detection of an ETV6-NTRK3 fusion during MD. NTRK fusions are associated with a >95% rate of malignancy and more aggressive tumour behaviour, although hyperplastic nodules carrying an NTRK fusion have also been reported [712, 745]. A possible explanation for the false-negativity of this semi-cystic nodule may be found in its size: as its solid component was only 8 mm, its detection may have been limited by the detection limits of the [18F]FDG-PET/CT scanner. False-negativity in molecular diagnostics In case of molecular diagnostics, false-negative results may either concern the presence of a rarer molecular alteration that is not included in the applied molecular panel, detected molecular alterations that are associated with a lower risk of malignancy, nodule sampling error, and/or issues with the DNA/RNA quantity or quality of the tissue sample. Although much of the thyroid cancer genome remains to be unravelled, the number of unknown molecular alterations in thyroid neoplasms is undoubtedly decreasing. Over the past decade, molecular panels have increasingly been expanded with newly detected gene alterations. For example, ThyroSeq v3 assesses 112 thyroid cancer-related genes for molecular alterations included copy number alterations for oncocytic lesions, whereas the ThyroSeq v2.1 only assessed 13 potential somatic mutations and 42 potential gene fusions [118, 490]. The three NGS panels that we applied in our studies targeted 87 thyroid cancer-related genes for somatic mutations, 19 genes for possible fusions, and 1,500 single nucleotide polymorphisms (SNP) for possible copy number alterations
RkJQdWJsaXNoZXIy MTk4NDMw