463 A clinically applicable molecular classification of oncocytic cell thyroid nodules 11 Discussion In the current study, we described the CNA patterns that were observed on CNA-LOH analysis in benign and malignant OCN using a limited, 1,500 SNP GWLOH NGS panel. With this method that is feasible for daily clinical practice, we are able to distinguish four CNA patterns and establish a molecular diagnosis with an increasing risk of malignancy. The assessment of the CNA patterns in a patient cohort confirmed that GH type CNA is found primarily in OCA but to a lesser extent also in OA. GH type alterations with possible endoreduplication were reserved for OCA, mi-OCA as well as wi-OCA, and mainly those with more extensive chromosomal losses. These results are in accordance with previous studies that reported on the early and late events in near-whole genome haploidization [343, 483, 484, 649, 674-676]. Only the loss of chromosome 18 was infrequently observed in the current study, in contrast to observations by Corver et al. and Ganly et al. [483, 649, 674]. RCI type CNA, which have less frequently been described in literature, were foremost associated with benign disease in the current study [649, 673]. Point mutations were rarely observed and gene fusions were not found in our cohort, endorsing that CNA are likely the main molecular drivers in OCN. CNA-LOH analysis may be of great added value in the (preoperative) diagnosis and risk stratification of OCN in clinical practice, aiding multidisciplinary patient management decisions. Case 23 illustrated that CNA-LOH analysis can be pivotal in identifying aggressive biological potential in OCN, especially if morphological histopathological features of malignancy are lacking. Although infrequently reported, metastases of OCN that were initially morphologically diagnosed as OA are notorious [670, 671]. In hindsight, based on the molecular profile of the original tumour, treating the original lesion of case 23 as an OCA would have been justified. Unfortunately, these molecular techniques were not available yet at the time of the original diagnosis. Case 16 illustrated that CNALOH analysis may also contribute to the risk reduction and avoid possible overtreatment of OCN with an equivocal histopathological diagnosis of OCA. Based on the molecularly benign CNA pattern that was observed in this case, indolent biological behaviour or even a benign nature of the neoplasm may be expected [649]. Following the results of the current and previous studies, initial total thyroidectomy could be considered instead of diagnostic hemithyroidectomy for oncocytic cell lesions with (extensive) GH type alterations and (suspected) endoreduplication (i.e., a malignant molecular diagnosis) [343, 483, 484, 674-676]. In less extensive GH type alterations without (suspected) endoreduplication (i.e., an uncertain malignant molecular diagnosis), diagnostic hemithyroidectomy is recommended to obtain a definitive diagnosis. When RCI type CNA are observed, hemithyroidectomy should also be considered. Although associated with biologically benign disease in the current study, evidence regarding RCI type CNA is still limited and future studies are needed to confirm our observations [649, 673].
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