Hürthle Cell Tumors of the Thyroid

Abstract

Abstract Hurthle cell carcinoma (HCC) of the thyroid gland is a unique tumor accounting for ~\xa03% of all thyroid cancers. HCC is a form of oncocytic neoplasia that is characterized histopathologically by granular eosinophilic staining due to a striking accumulation of mitochondria. Although HCC is a form of well-differentiated thyroid cancer, it has a tendency toward aggressive clinical behavior, including distant metastases and radioactive iodine resistance. Despite poor iodine uptake, HCC tumors show strong fluorodeoxyglucose avidity on positron emission tomography (PET) imaging, a feature that underscores the metabolic reprogramming present within these distinct cancers. Until recently the genetic driver events in HCC were unknown. In fact HCC was often characterized by its notable absence of mutations in classic thyroid cancer driver genes such as BRAF, RAS family members, and the PAX8-PPAR-gamma fusion gene. Recent whole-exome sequencing studies, however, have jointly analyzed the nuclear and mitochondrial genomes of HCC and found unique molecular alterations. Most notable among these changes are the widespread loss of heterozygosity across multiple chromosomes and the recurrent disruptive mitochondrial DNA mutations in genes encoding complex I subunits—the first step in mitochondrial respiration. This more comprehensive understanding of the genomic landscape of HCC may pave the way for the discovery of novel therapies for this disease whose current management includes total thyroidectomy for primary disease and empiric use of U.S. Food and Drug Administration (FDA)-approved targeted agents for thyroid cancer in the metastatic setting.