Genetics, Diagnosis, and Management of Hürthle Cell Thyroid Neoplasms

Abstract

Hürthle cell lesions have been a diagnostic conundrum in pathology since they were first recognized over a century ago. Controversy as to the name of the cell, the origin of the cell, and even which cells in particular may be designated as such still challenge pathologists and confound those treating patients with a diagnosis of “Hürthle cell” anything within the diagnosis, especially if that anything is a sizable mass lesion. The diagnosis of Hürthle cell adenoma (HCA) or Hürthle cell carcinoma (HCC) has typically relied on a judgement call by pathologists as to the presence or absence of capsular and/or vascular invasion of the adjacent thyroid parenchyma, easy to note in widely invasive disease and a somewhat subjective diagnosis for minimally invasive or borderline invasive disease. Diagnostic specificity, which has incorporated a sharp increase in molecular genetic studies of thyroid tumor subtypes and the integration of molecular testing into preoperative management protocols, continues to be challenged by Hürthle cell neoplasia. Here, we provide the improving yet still murky state of what is known about Hürthle cell tumor genetics, clinical management, and based upon what we are learning about the genetics of other thyroid tumors, how to manage expectations, by pathologists, clinicians, and patients, for more actionable, precise classifications of Hürthle cell tumors of the thyroid.

Hürthle Cell Carcinoma: Single Center Analysis and Considerations for Surgical Management Based on the Recent Literature

“…Both patients died two and four years after diagnosis respectively. A particular challenge for systemic treatment is the general lack of actionable somatic alterations in HCC ( 29 ). Alterations amenable to targeted therapy seem to be rare ( 30 , 31 ).…”

Mitochondrial-encoded complex I impairment induces a targetable dependency on aerobic fermentation in Hürthle cell carcinoma of the thyroid

“…Mitochondrial accumulation and evidence of metabolic rewiring are defining features of HTC, yet approximately 40% of HTC tumors do not harbor discrete mutations in complex I subunits (Ganly et al, 2022; Ganly et al ., 2018; Ganly and McFadden, 2019; Gopal et al ., 2018; McFadden and Sadow, 2021). This raises the question whether all HTC tumors exhibit functional ETC impairment.…”

“…Hürthle cell carcinoma of the thyroid (HTC, also called oncocytic carcinoma of the thyroid) is an oncocytic form of thyroid cancer characterized by mitochondrial accumulation, increased glucose uptake, poor radioiodine concentration, and distinct patterns of metastatic spread (Ganly and McFadden, 2019; McFadden and Sadow, 2021). We and others (Ganly et al ., 2018; Gopal et al ., 2018b) have reported that mtDNA-encoded mutations in complex I of the mitochondrial ETC occur in approximately 60% of HTC tumors.…”

Molecular Alterations and Comprehensive Clinical Management of Oncocytic Thyroid Carcinoma

“…In addition, patients with encapsulated OTC with extensive vascular invasion were more likely to recur than those with similarly characterized FTC. Still, whether OTC is a more aggressive pathologic entity remains unclear …”