Thyroid nodules are distinct lesions found within the thyroid parenchyma [1] . Most thyroid nodules are asymptomatic and are often discovered incidentally through ultrasound imaging, with prevalence rates ranging from 33% to 60% in adults, particularly in Asia and Europe [2] [3] . Other studies suggest that up to 65% of adults may have thyroid nodules detected via high-resolution ultrasound, with prevalence increasing with age and being more common in females than in males [4] . While the majority of thyroid nodules are benign, such as follicular adenomas, cysts, and colloid nodules, approximately 5% - 15% are malignant, including papillary, medullary, follicular, and anaplastic carcinomas [4] [5] . Although surgical intervention remains the standard treatment for malignant tumors, it is associated with complications like hypothyroidism, voice changes, hypocalcemia, and scar formation. As a result, radiofrequency ablation (RFA) has emerged as a minimally invasive and effective alternative for treating thyroid tumors [2] .

RFA utilizes thermal energy to induce coagulative necrosis within targeted tissue, thereby causing inactivation or destruction of the tumor and leading to a reduction in nodule volume and symptom relief. This approach offers several advantages, including faster recovery, preservation of normal thyroid function, and cost-effectiveness [6] . The procedure is guided by ultrasound imaging. Grayscale ultrasound is employed to assess RFA efficacy by evaluating B-mode sonographic characteristics to determine either complete or partial inactivation [7] . This is further supported by color Doppler and Contrast-Enhanced Ultrasound Scan (CEUS), which assess nodule viability. These imaging techniques improve diagnostic accuracy, facilitate comprehensive post-treatment monitoring, and support effective clinical management [8] [9] . RFA avoids many of the risks associated with traditional surgery, such as hypothyroidism and permanent voice changes, making it a more attractive option for patients [10] .

Thyroid hormones, including free thyroxine (FT4) and free triiodothyronine (FT3), are essential for growth, development, and metabolic regulation. Their production and release are controlled by thyroid-stimulating hormone (TSH). Changes in these hormones following RFA of benign and malignant thyroid tumors can offer valuable insight into the procedure’s impact on thyroid function and overall endocrine health [11] While benign thyroid nodules typically maintain normal hormonal levels after RFA, indicating preserved thyroid function, malignant nodules may exhibit alterations in hormone levels due to the extensive tissue destruction required to eliminate malignant cells [11] [12] .

Understanding the predictors of inactivation of thyroid nodules following RFA and the hormonal dynamics thereafter is imperative in leading to more effective patient management strategies and better clinical outcomes for benign thyroid nodules. Therefore, this study evaluated the predictors of inactivation of benign thyroid nodules using RFA through assessing the nodule sonographic characteristics and the post-RFA hormonal response.

Records of 375 nodules from 373 patients with benign thyroid masses were retrieved from January 2022 to January 2024. After excluding 85 patients who had no cytology results, 25 who underwent mass resection and 193 with no thyroid hormone results, 72 were eligible and so included in the analysis. Figure 1 . Demographic characteristics of all enrolled patients (n = 72) are summarized in Table 1 . Before RF ablation, the mean largest diameter of the thyroid nodules was 1.3 ± 1.1 (range 0.2 - 5.4) cm, with a mean volume of 1.1 ± 1.9 (range 0.002 - 8.675) cm³. Majority of the nodules were regular in shape (59.7%), had clear margins (51.4%) and were solid in composition (91.7%). All patients tolerated RF ablation and none underwent surgery after ablation.

This retrospective study investigated the degree of inactivation in benign thyroid nodules and the hormonal effects following RFA. Existing literature largely supports the efficacy of RFA in managing thyroid tumors, primarily benign nodules and select malignant cases, with minimal or no significant impact on thyroid function [13] - [15] . In our analysis, we examined key sonographic parameters that confirm complete or partial inactivation, as well as factors that may independently predict RFA success in benign thyroid nodules. Our findings highlighted vascularity (presence or absence) and nodule calcification as key determinants of the extent of nodule inactivation.

Our study identified nodule vascularity as a key sonographic finding. Color Doppler imaging revealed that nodules with internal and peripheral blood flow were associated with partial inactivation (p < 0.001), while completely inactivated nodules exhibited minimal to no vascularity. In similar studies, Motaghed et al. [16] found hyper-vascular benign nodules were 4.1 times more likely to achieve RFA success, while Deandrea et al. [17] linked hyper-vascularity to higher volume reduction rates, attributing success to coagulative necrosis and subsequent cell death. These findings contrast with ours, which indicated that partially inactivated nodules exhibited greater vascularity than completely inactivated ones. We attribute this discrepancy to the fact that RFA uses an electrode to generate heat that destroys nodule cells. Hypervascular nodules, however, require more energy for ablation due to the heat sink effect and perfusion-mediated cooling, as described by So Lyung Jung [18] and Navin et al. [19] . The cause of this inconsistency remains unclear, and further research is needed to elucidate the underlying mechanisms.

Furthermore, the presence of calcification was associated with a reduced likelihood of achieving complete inactivation (p = 0.040). This finding aligns with that of Li et al. [20] who reported that macro-calcifications were linked to lower VRR in calcified benign nodules compared to non-calcified nodules. This they said could be due to challenges in penetrating dense calcifications, which hinder effective heat conduction to the targeted tissue, as well as the inability to monitor the electrode tip within areas of acoustic shadowing.

Other factors, such as shape (regular or irregular), margins (clear or unclear), and composition, showed no significant impact on complete versus partial inactivation. While regular shapes may distribute ablation energy more evenly, irregular masses are harder to eliminate due to uneven borders and invasive behavior. The inconclusive results in our study could stem from a small sample size or patient similarity. Although RFA is effective for all thyroid nodule types, studies indicate greater volume reduction and lower recurrence rates in predominantly cystic nodules [21] . Conversely, our findings showed that nodule composition (solid versus mixed) did not significantly influence RFA success, likely due to varying ablation energy requirements.

The impact of RFA on thyroid function remains uncertain, despite well-documented evidence of benign nodule inactivation. Theoretically, RFA can alter thyroid function by inducing hyperthyroidism through hormone release from ablated tissue or hypothyroidism due to extensive tissue destruction [21] . Long-term studies have generally shown no significant hormonal changes, with FT3, FT4, and TSH levels remaining normal up to 12 months post-RFA [22] [23] . Wang et al. [14] also reported stable thyroid function one month after thermal ablation in low-risk unifocal PTMC cases. However, short-term thyroid function trends are inconsistent. Some reports document temporary hypothyroidism, such as elevated TSH levels immediately after RFA, which typically resolve within a year [21] [24] [25] . Hussain et al. [26] observed significant FT4 reductions post-RFA in non-functioning nodules, suggesting a potential indicator of hypothyroidism. Wang et al. [27] further reported increased hormone levels within a week post-RFA, especially in patients with diabetes, alongside cases of overt thyrotoxicosis, subclinical thyrotoxicosis, and long-term subclinical hypothyroidism. In our study, no significant changes in FT3 or FT4 were observed over 6 months, though borderline TSH elevations were noted at 3 and 6 months. These variations may result from unmasked subclinical hypothyroidism or incomplete ablation. Long-term follow-up beyond two years is recommended to ensure patient reassurance and guide future management.

Our study provides valuable insights into key sonographic parameters influencing complete and partial inactivation of benign thyroid nodules post-RFA. It also highlights the importance of hormonal follow-ups to guide patient expectations regarding thyroid function outcomes. However, the study has some key limitations: It was a single-institution retrospective analysis with no pre-RFA nodule data, had a small sample size which may affect statistical power, and had a short follow-up duration (6 months), excluding long-term hormone monitoring. A well-designed, prospective cohort study is needed to further validate these findings.

In conclusion, this study demonstrated that therapeutic RFA achieves high rates of complete inactivation in benign thyroid nodules. The extent of inactivation is primarily influenced by nodule vascularity and calcifications. While no significant impact on thyroid function was observed, mild upper borderline TSH changes at 3 and 6 months underscore the need for long-term monitoring. To further substantiate these results, a larger, well-designed prospective multicenter cohort study is essential, particularly exploring combination therapies for malignant thyroid tumors.

We sincerely thank Dr. Wei for his guidance in data collection and language translation, and Dr. Agnes Kanusya for the insightful edits. We also appreciate Zhongnan Hospital of Wuhan University for granting us permission to conduct this study and providing essential material and technical support.

Conceptualization, WE; methodology, WE and MW; software, WE. Formal analysis, WE. Investigation; WE and JYC; resources, MW. Data curation. WE, Writing—original draft preparation, WE; writing—review and editing, JYC EAS, MP. Visualization, WE. Supervision, JYC; funding acquisition, WE. All authors have read and agreed to the published version of the manuscript.

This study was approved by the Zhongnan Hospital of Wuhan University Research Ethics Committee.

This study was supported by grants from the Hubei Provincial Key Research and Development Project. Grant No. 2023BCB024.