The biology and the genetics of Hürthle cell tumors of the thyroid

Abstract

The biology and the genetics of Hü rthle cell tumors are reviewed starting from the characterization and differential diagnosis of the numerous benign and malignant, neoplastic and nonneoplastic lesions of the thyroid in which Hü rthle cell transformation is frequently observed. The clinicopathologic and molecular evidence obtained from the comparative study of the aforementioned conditions indicate that Hü rthle cell appearance represents a phenotype that is superimposed on the genotypic and conventional histopathologic features of the tumors. Hürthle cell tumors differ from their non-Hü rthle counterparts regarding the prevalence of large deletions of mitochondrial DNA (mtDNA), mutations of mtDNA genes coding for oxidative phosphorylation (OXPHOS) proteins (namely mutations of complex I subunit genes) and mutations of nuclear genes coding also for mitochondrial OXPHOS proteins. Such mitochondrial alterations lead to energy production defects in Hü rthle cell tumors; the increased proliferation of mitochondria may reflect a compensatory mechanism for such defects and is associated with the overexpression of factors involved in mitochondrial biogenesis. The mitochondrial abnormalities are also thought to play a major role in the predisposition for necrosis instead of apoptosis which seems to be blocked in most Hü rthle cell tumors. Finally, the results obtained in experimental models using cybrid cell lines and the data obtained from histopathologic and molecular studies of familial Hü rthle cell tumors are used, together with the aforementioned genetic and epigenetic alterations, to progress in the understanding of the mechanisms through which mitochondrial abnormalities may be involved in the different steps of thyroid carcinogenesis, from tumor initiation to metastization.

Thyroid Hürthle cell tumors: research of potential markers of malignancy

“…The WHO defines HCT as a thyroid tumor consisting of at least 75 % of oxyphilic cells within the nodule [1][2][3]. HCT is characterized by the cytoplasmatic accumulation of mitochondria that frequently, on electron microscopy, displays abnormal morphology [1,2,4]. Cytological study subsequent to fine needle biopsy can identify the presence of oncocytic tumor cells, but does not distinguish benign from malignant tumors even though 30 % of HCT are malignant [2,5,6].…”

“…A gene (GRIM-19) locus linked to this familial HCT has been isolated on chromosome 19p13.2 [20]. GRIM-19 gene produces a 16-kDa protein localized within the nucleus and mitochondria [4,12,14,17]. Its function is exerted through two mechanisms: (1) assembly and function of the complex I of mitochondrial respiratory chain and (2) apoptosis induction upon interferon and retinoic acid treatment [14,15].…”

“…Its function is exerted through two mechanisms: (1) assembly and function of the complex I of mitochondrial respiratory chain and (2) apoptosis induction upon interferon and retinoic acid treatment [14,15]. It has been suggested that mutations on GRIM-19 gene may play a role in carcinogenesis and specifically in HCT [4,12,16,17].…”

PVALB diminishes [Ca2+] and alters mitochondrial features in follicular thyroid carcinoma cells through AKT/GSK3β pathway

“…Although HCC are believed to be a variant of follicular carcinomas, a more aggressive behavior has been reported (Montone et al 2008, Maximo et al 2012. Considering this and that Hürthle cells show low uptake of iodine and, therefore, do not respond well to conventional treatment (Montone et al 2008), we raised the question as to whether PVALB could be a target for HCC therapy.…”

“…Hürthle cell neoplasms, both benign and malignant, should be composed of at least 75% Hürthle cells (Montone et al 2008), whcih are large cells with abundant cytoplasm containing accumulation of morphologically abnormal mitochondria (Montone et al 2008, Maximo et al 2012, Ferreira-da-Silva et al 2015. Additionally, it has been suggested that Hürthle cell neoplasms may show dystrophic calcifications (Montone et al 2008).…”