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.

Keywords: Hürthle cell; Hürthle cell carcinoma; oncocytic; thyroid; thyroid cancer.

Figure 1

Morphological Controversies. Hematoxylin and eosin stains of Hürthle cell carcinoma. Endothelial wrapping or bulging of tumor into endothelial lined spaces raises the question of lymphatic invasion. Tumor bulging (A, arrowheads, 100X) is controversial with some requiring presence of intravascular thrombi. The band of fibrosis (A, discontinuous line) raises the question of biopsy site versus capsule with invasion with some discussion of hemosiderin deposition (not seen here) to indicate needle track. Tumor nodule with surrounding endothelial cells (B, arrowheads, 400X) in a space adjacent to the main tumor mass raises the possibility of capsular invasion versus vascular invasion versus focus of adjacent tumor in an unencapsulated lesion. Trabecular growth of true Hürthle cells (C, 400X) with round nuclei, pale nucleoplasm and prominent, centrally located nucleoli in Hürthle cell carcinoma. In the same tumor, with trabecular growth (D, 40X), shows an adjacent focus of overt vascular invasion in a large vessel located within the adjacent skeletal muscle (asterisks).

Figure 2

Reactive Changes in Hürthle Cell Neoplasia. Among the diverse reactive changes seen with Hürthle cell neoplasia (hematoxylin and eosin stain), especially post traumatic, are cystification (A, 20X magnification), ossification (B, 20X magnification), and capsular irregularity with coarse calcification (C, 40X magnification). Cystic changes due to hypoxia-related cellular drop out lead to papillary architectural formations at low power, lacking fibrovascular cores (A) but retaining Hürthle cell morphology and typically at least focal follicular architecture (A, inset, 1000X magnification). Exquisite hypoxia sensitivity can lead to complete ossification (B), post-traumatic, of Hürthle cell tumors, occasionally with no residual cells or with rare clusters that may exhibit Hürthle cell features with associated nuclear atypia (B, inset, 1000X magnification). An additional feature, especially in tumors with thicker capsules, is intracapsular so-called “coarse” or “egg shell” calcifications which can distort the lesional growth pattern at the periphery and conferring a pseudoinvasive growth pattern (C).

Figure 3

Widely invasive Hürthle cell carcinoma with high-grade features, hematoxylin and eosin stain. Multinodular growth of the Hurthle cell carcinoma into adjacent thyroid with no circumscription leads to non-controversial diagnosis of widely invasive Hurthle cell carcinoma (A, 40X). Collections of hyperchromatic, irregularly shaped nuclei with hypereosinophilic colloid, so-called burgeoning or incipient necrosis (B, circles, 400X). Frequent mitoses and scattered irregular (tripolar) mitoses (C, circle, 400X) and variably retained prominent nucleoli. Tumor metastasis to lateral neck lymph nodes (D, 20X), following a typical pattern of metastasis in Hürthle cell malignancies.

Figure 4

Hürthle cell carcinomas harbor recurrent mutations in genes encoding complex I of the electron transport chain in the mitochondrial genome (mtDNA), widespread loss of chromosomes leading to a near-haploid state, and recurrent mutations in several oncogenes and tumor suppressor genes, albeit at a low frequency. (Reproduced with permission from Gopal, RK, Kübler K, Calvo SE et al. Widespread chromosomal losses and mitochondrial DNA alterations as genetic drivers in Hürthle cell carcinoma. Cancer Cell 2018; 34:242-255.e5).