Date of Award

January 2025

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Adriana Ramirez

Abstract

Thyroid neoplasms, both benign and malignant, significantly contribute to healthcare burden in the United States. Oncocytic neoplasms (ON), previously classified as Hürthle-cell neoplasms and comprising oncocytic adenoma (OA) and oncocytic carcinomas (OC), represent a rare subset of follicular cell-derived thyroid pathology, accounting for 3–7% of all thyroid malignancies. OC are considered more aggressive with worse prognosis due to higher rates of recurrence as well as inherent resistance to radioactive iodine, the first line of adjunct therapy for well-differentiated thyroid cancers. Conversely, papillary thyroid carcinoma (PTC), another follicular cell-derived thyroid cancer, constitutes over 90% of thyroid cancer cases and is characterized by an indolent course and favorable prognosis. This study investigates the prevalence, molecular characteristics, and concurrent presence of PTC in patients diagnosed with ONs using data from the Yale Endocrine Surgery (YES) Registry.A synergistic relationship between the development of ON and PTC was hypothesized, aiming to account for an elevated prevalence of PTC observed among patients with oncocytic pathology (30.9%) compared with rates previously reported in the literature (10-15%). A retrospective case-control study design was employed, analyzing patient demographics, tumor characteristics, and molecular testing results from 120 patients diagnosed with ON. Cases of concurrent PTC were stratified as homotopic (same anatomic locus) or heterotopic (distinct anatomic loci). Findings revealed that male sex was associated with a higher prevalence of concurrent PTC (OR=1.7, p=0.10), although statistical significance was not achieved due to sample size limitations. OC were significantly larger than OA (3.9 cm>2.3 cm, p=0.0002) but showed no significant association with an increased likelihood of concurrent or homotopic PTC compared to OA. Molecular testing was performed in 45.8% of cases, with Thyroseq being the most utilized modality. Analysis of molecular testing results corresponding to an oncocytic neoplasm on final pathology revealed common genetic variations known to be associated with oncocytic neoplasms, such as NRAS, EIF1AX, and copy number variants – notably not including BRAF mutations. Molecular profiles did not differ significantly with the presence of OC, concurrent PTC, or homotopic PTC. Logistic regression models evaluating age, sex, ON subtype, and tumor size failed to establish predictive relationships for concurrent or homotopic PTC prevalence. Furthermore, no molecular evidence supported a causal link between ON and PTC. The observed prevalence of homotopic PTC in patients undergoing total thyroidectomy was equivalent to that of heterotopic PTC. Collectively, these findings are collectively insufficient to suggest a causal relationship between the oncocytic pathology and the development of PTC. Importantly, the hypotheses examined in this thesis assumed that causality would require anatomic proximity. It is important to note that any intrathyroidal pathology could cause significant changes to the entire microenvironment of the thyroid gland, challenging the validity of this axiom. This study highlights critical limitations – namely selection bias, incomplete molecular testing, and small sample sizes hampering study power. Future endeavors should focus on studying larger, more diverse databases, utilizing methods capable of properly identifying homotopic pathology, and developing longitudinal studies that include patients managed conservatively to correctly identify the clinical utility of molecular testing of ONs and their relationship with PTC. In summary, while the elevated prevalence of PTC in ON cases warrants further investigation, our findings are insufficient to support a causal relationship that relies on anatomic proximity.

Comments

This is an Open Access Thesis.

Download
Open Access

This Article is Open Access

Share

COinS