466 chapter 11 Finally, CNA-LOH analysis results should be carefully interpreted in the context of other clinicopathological characteristics, including nodule size, for example. Larger nodule size (>4 cm, in particular) has previously been associated with a higher risk of malignancy in OCN and worse prognosis in OCA [484, 533, 690]. Although the current study found no statistically significant difference in nodule size between benign and malignant lesions, nodules with GH type CNA and possible endoreduplication were significantly larger than GH type nodules without endoreduplication. CNA-LOH analysis may resolve important bottlenecks in the preoperative differentiation of OCN. Besides their unique molecular alterations, OCN oftentimes also show atypical results and lower diagnostic accuracy on other preoperatively applied diagnostics, including ultrasound and positron emission tomography/computed tomography (PET/CT) using 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) [25, 501, 519]. [18F]FDG-PET/CT visualizes (increased) metabolic activity in tissues and is successfully applied for the diagnosis, staging and monitoring of many types of cancers [468]. A visually negative [18F]FDG-PET/CT accurately differentiates between benign and malignant cytologically indeterminate thyroid nodules. This, however, does not apply to nodules with oncocytic cell cytology, which are almost exclusively strongly [18F]FDG-positive, likely related to their abundance of mitochondria [501]. Due to the increased use of imaging techniques for indications unrelated to the thyroid, thyroid nodules are detected in up to 65% of the general population [464, 581]. This includes [18F]FDGpositive thyroid incidentalomas, which are found in approximately 2% of [18F]FDG-PET/CT scans with an approximate 31% malignancy rate [451]. The exact number of oncocytic cell lesions among these incidentalomas is unknown, but may be substantial due to the pronounced [18F]FDG-positivity in these nodules [480, 501]. In our screened patient population, 11 of 48 (23%) presented with a PET/CT thyroid incidentaloma. Six of 11 (55%) patients did not undergo surgery, most frequently due to (oncological) comorbidities that were the indication for the [18F]FDG-PET/CT. In patients with considerable comorbidities, molecular testing including CNA-LOH analysis may aid the considerations and risks of withholding surgery. The main limitation of our study is its retrospective design, potentially causing bias. Selection bias may have resulted in a nonrepresentative patient cohort if CNA-LOH analysis and/or thyroid surgery were only selectively performed. Moreover, some of the included patients were consultations from community hospitals, specifically referred to our hospital for CNA-LOH analysis. In addition, the relatively small sample size of our cohort limited further statistical analysis of the observed CNA patterns in relation to clinical and histopathological characteristics. The current study was not designed to assess diagnostic performance of the GWLOH panel. Larger, prospective validation studies are desired to explicate the CNA-appurtenant risk stratification of OCN and assess (preoperative) diagnostic accuracy parameters of CNA-LOH analysis, including differences in test performance between cytological and histopathological tissue specimens. Such cohorts could also
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