443 A clinically applicable molecular classification of oncocytic cell thyroid nodules 11 Introduction Thyroid oncocytic cells are follicular-derived oncocytic cells that are characterized by granular, eosinophilic cytoplasm due to an abundance of mitochondria. Their nuclei are enlarged and rounded, with prominent nucleoli [503]. Before the introduction of the 2023 WHO classification referred to as Hürthle cell neoplasms, oncocytic cell neoplasms (OCN) are defined as thyroid neoplasms composed of >75% oncocytic cells and include oncocytic thyroid adenoma (OA) and carcinoma (OCA) [20-22]. OCN are distinct from other types of thyroid nodules or differentiated thyroid carcinoma in their biological and clinical behaviour. OCA, in particular widely invasive OCA, typically show more aggressive behaviour and less favourable prognosis than their non-oncocytic cell follicular counterparts, including higher rates of extra-thyroidal extension, radioiodine-refractory disease, distant metastases, and mortality [504, 668]. Historically defined as a subtype of follicular thyroid carcinoma, the 2017 WHO classification has recognized OCA as a completely separate entity in follicular neoplasia [20]. Distinguishing benign from malignant OCN may be complex: cytological differentiation is not possible as (histopathological) assessment of capsular and vascular invasion is required, interobserver variability is observed, and metastases of OCN with an initial morphological diagnosis of OCA have been described [18, 669-671]. In addition, oncocytic cell metaplasia/ hyperplasia in the thyroid should be clearly distinguished from true OCN, as it is different in both origin and genetic alterations. It may occur in lymphocytic thyroiditis, oncocytic variant papillary thyroid carcinoma, medullary thyroid carcinoma, parathyroid lesions, and non-thyroid metastasis [669, 672]. Whole-chromosome instability is a main characteristic of the tumorigenesis in OCN. The process might be driven by a continuous redox imbalance due to the accumulation of malfunctioning mitochondria causing mitotic errors, leading to near-whole genome haploidization (GH, i.e., consistent with an A0 genotype) with subsequent endoreduplication (i.e., genome doubling, an AA genotype or multiple thereof). These copy number alterations (CNA) seem to occur stepwise and in patterns in the progression from OA to OCA [649]. More extensive loss of heterozygosity (LOH) and endoreduplication are associated with progression of disease and worse prognosis [343, 483, 484, 673-676]. Corver et al. previously described the LOH of chromosomes 1, 2, 8, 9, 18 and 22 as early events and the additional loss of chromosomes 2, 3, 6, 11, 14-16, and 21 as later events indicating progression of disease, with the loss of chromosomes 1-4, 6 and 11 as the minimum signature of OCA [649]. Similar patterns were observed by Ganly et al., who described the LOH of chromosomes 2, 9, 11 and 18 as early events [674]. The LOH of chromosome 7 is never observed, likely due to maternal- and paternal-imprinted genes important for survival [677]. Chromosomes 5, 12 and 20 are also frequently spared [649, 674]. To a lesser extent, these characteristic CNA patterns are also described in part of the OA [484, 649, 673, 678, 679]. Other, reciprocal patterns of imbalanced chromosomal gains, consistent with genotype AAB, have also been observed in OA [649, 673]. In addition, driver point mutations (e.g., TERT promoter or TP53) have also been described in OCA [342, 484, 649, 674, 676, 680, 681].
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