Authors: Wen-Hui Chan, Pi-Ling Chiang, An-Ni Lin, Yen-Hsiang Chang, Wei-Che Lin
Categories: Review Article, Bethesda III, Bethesda IV, Radiofrequency ablation, Thermal ablation, Thyroid nodule
Source: Ultrasonography
Doi: 10.14366/usg.24083
The diagnosis and management of Bethesda III and IV thyroid nodules remain clinical dilemmas. Current guidelines from academic societies suggest active surveillance or diagnostic lobectomy. However, the extent of surgery is often inappropriate, and a considerable percentage of patients experience under- or over-treatment. Thermal ablation has gained popularity as a safe and effective alternative treatment option for benign thyroid nodules. This review explores the feasibility of thermal ablation for Bethesda III or IV thyroid nodules, aiming to preserve the thyroid organ and avoid unnecessary surgery. It emphasizes individualized management, the need to consider factors including malignancy risk, clinical characteristics, and sonographic features, and the importance of supplemental tests such as repeat fine needle aspiration cytology, core needle biopsy, molecular testing, and radioisotope imaging.
Keywords: Thyroid nodule, Radiofrequency ablation, Thermal ablation, Bethesda III, Bethesda IV
Thyroid nodules are common in day-to-day clinical practice and have been increasingly identified over the past three decades, mainly due to the widespread introduction of medical ultrasonography (US) [1]. The prevalence of thyroid nodules in the general population is variable, with estimates as high as 67% depending on the method of detection used (palpation, US, or autopsy) [2,3].
Most thyroid nodules are benign, and only approximately 5%-15% of evaluated nodules are proven to be malignant [4]. Fine needle aspiration (FNA) cytology of the thyroid nodule is an accurate and cost-effective method for distinguishing between benign and malignant thyroid nodules, playing a crucial role in diagnosis [1,5]. The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is used worldwide as a standardized reporting system for thyroid FNA cytology specimens [5]. Specimens are classified as belonging to one of six categories, from category I (nondiagnostic) to category VI (malignant). In about 70%-80% of cases, TBSRTC reliably establishes whether a nodule is benign (Bethesda II), suspicious for malignancy (Bethesda V), or malignant (Bethesda VI) [5]. However, gray zones exist due to conflicting data on the risk of malignancy and the clinical management of nodules classified under Bethesda category III (atypia of undetermined significance) and Bethesda IV (follicular neoplasm) [5]. The reported risks of malignancy in these indeterminate cytologic categories range significantly, from 13%-30% to 23%-34%, respectively [5].
Current guidelines recommend a thorough evaluation of clinical and sonographic findings for Bethesda III and IV nodules, including supplemental repeat FNA cytology or molecular testing (where available) for malignant risk assessment; with diagnostic surgery as the final resolution [6-12]. Nevertheless, regular follow-up or repeated FNA/core needle biopsy (CNB) procedures may cause psychological distress to individuals with these cytologically indeterminate thyroid nodules. Molecular testing of FNA samples has been used to improve the malignancy risk stratification; however, it is not widely available worldwide at present. Diagnostic surgery has been frequently deemed unnecessary, as revealed by a recent study indicating that up to 68% of operations performed on patients with Bethesda III and IV nodules in the absence of molecular testing were ultimately shown to be futile [13]. In addition, surgery carries risks of complications, including scarring, recurrent laryngeal nerve injury, hypoparathyroidism, and hypothyroidism, which may require long-term thyroxine replacement therapy [14,15].
Thermal ablation has been introduced as a safe and effective alternative for treating thyroid nodules. Nonetheless, its use has been limited to those with benign cytology or as an adjunctive treatment for recurrent thyroid cancers [11,16,17]. The use of thermal ablation for Bethesda III and IV nodules remains debatable. A few studies have revealed that radiofrequency ablation (RFA) can be a safe and effective method to treat patients with Bethesda III and IV thyroid nodules [18-22]. However, a study demonstrated that two out of six patients (33%) with indeterminate cytology nodules undergoing RFA turned out to have minimally invasive follicular thyroid cancer and a follicular neoplasm of undetermined malignant behavior, respectively [23].
The purpose of this article is to review up-to-date clinical research on the diagnosis and management of Bethesda III and IV thyroid nodules, with a focus on the safety, efficacy, and future prospects of thermal ablation. This review aims to offer insights that will assist in clinical decision-making for the management of Bethesda III and IV nodules, as well as to explore the possibility of adopting a minimally invasive treatment approach.
Diagnostic thyroid lobectomy is the long-established standard of care for obtaining a definitive histologic diagnosis of Bethesda III and IV nodules. However, with the rapid advancement of diagnostic tools and increasing awareness of the importance of thyroid preservation, additional imaging or molecular tests in the preoperative clinical setting are more widely accepted in order to avoid unnecessary surgery. The following section discusses the utility of these non-invasive or minimally invasive tests, such as US risk stratification, radioisotope scans, repeat FNA cytology or CNB, and molecular testing.
US plays a pivotal role in the evaluation of thyroid nodules [24]. Several thyroid nodule US risk stratification systems (US RSS) have been proposed, for example, the American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi (AACE/ACE/AME US RSS) [8], the American College of Radiology (ACR TI-RADS) [25], the American Thyroid Association (ATA US RSS) [7], the British Thyroid Association [26], the European Thyroid Association (EU-TIRADS) [27], the Korean Society of Thyroid Radiology (K-TIRADS) [28], and the TIRADS by Kwak et al. [29]. The most widely used systems are the 2015 ATA US RSS and the ACR TI-RADS [7,25]. The 2015 ATA US RSS is a pattern-based system that classifies thyroid nodules into five categories based on US imaging features, with each pattern associated with an estimated malignancy risk ranging from benign (malignancy risk <1%) to high suspicion (malignancy risk >70%-90%) [7]. The ACR TI-RADS, in contrast, is a point-based scoring system where points are assigned based on five US features, and the total score determines the ACR TI-RADS category [25].
Several studies have addressed the role of US risk stratification in indeterminate thyroid nodules [30-36]. Barbosa et al. [31] reported a series of 140 indeterminate cytology thyroid nodules, in which nodules classified as Bethesda III and low-risk US category (very low, low, and intermediate suspicion by the ATA system or TI-RADS category 2, 3, or 4a) showed high negative predictive values (NPVs) of 94.3% and 94.1%, respectively. In contrast the high-risk US categories (high suspicion by ATA system or TI-RADS 4b, 4c, and 5) were significantly associated with malignancy, with odds ratios of 14.7 and 9.8, respectively [31]. In a systematic review and meta-analysis involving 14 studies and 2405 Bethesda III nodules, Gao et al. [32] reported that US had a pooled sensitivity of 75% and specificity of 48% when one suspicious US characteristic was present; however, when three suspicious US features were present, the sensitivity was 66% and specificity was 71%. Furthermore, two recent studies have shown that high-risk US features (e.g., marked hypoechogenicity, punctate echogenic foci, and nonparallel orientation) can effectively further subcategorize indeterminate suspicion thyroid nodules [37,38].
In terms of the performance of different US RSS, a recent systematic review and meta-analysis [39] involving 33 studies demonstrated that for Bethesda III nodules, when considering intermediate to high risk as positive, TIRADS by Kwak et al. [29] exhibited the highest sensitivity, while ATA US RSS showed the highest specificity, with the overall sensitivity and specificity values of 90% and 40%, respectively. Meanwhile, for Bethesda IV nodules, the overall sensitivity and specificity were 64% and 40%, respectively. Nevertheless, the number of studies available was insufficient to perform a quantitative analysis of each US RSS for Bethesda IV nodules [39].
In summary, US RSS along with TBSRTC may aid in the triage of Bethesda III and IV thyroid nodules. A conservative approach may be adopted for Bethesda III nodules with a low-risk US pattern, while molecular testing and diagnostic surgery should be considered for Bethesda IV nodules with a high-suspicion US pattern.
Various radioisotope imaging techniques have been introduced to differentiate between benign and malignant cytologically indeterminate thyroid nodules. ^99m^Tc-methoxy-isobutyl-isonitrile (^99m^Tc-MIBI) thyroid scintigraphy has been used for risk stratification of Bethesda III and IV nodules (Fig. 1). An early meta-analysis including 21 studies showed that ^99m^Tc-MIBI scintigraphy is a sensitive diagnostic tool for predicting malignancy, with pooled sensitivity and specificity values of 85.1% (95% confidence interval [CI], 81.1% to 88.5%) and 45.7% (95% CI, 42.7% to 48.7%), respectively [40]. A study introduced a more novel approach using both visual pattern assessment and quantitative MIBI washout index (WOind) [41]. The study reported overall sensitivity and specificity values of 100% and 90.9%, respectively, and both reached 100% when excluding Hürthle cell nodules [41]. The formula for WOind is provided in the Supplementary Text 1 [41].
Fig. 1. A 43-year-old man presented with a solitary nodule in the left thyroid gland.A. Thyroid ultrasonography (US) reveals a left-sided solid iso-to-hypoechoic mass measuring 6.05×3.96 cm with smooth margins and no suspicious features, classified as a Thyroid Imaging Reporting and Data System (TIRADS) category 4 nodule. Two fine needle aspirations were performed, both yielding Bethesda category 4 results. B, C. ^99m^Tc-methoxy-isobutyl-isonitrile (^99m^Tc-MIBI) thyroid scintigraphy was conducted at 10 (early) and 60 (late) minutes after tracer administration. Quantitative analysis using the washout index (WOind) method yielded a calculated WOind of -35.1%, which was considered indicative of intermediate risk according to a previous study [41]. BG, background; THY, thyroid nodule. D. Combining the cytology report, US risk stratification, and ^99m^Tc-MIBI WOind value, the patient underwent total thyroidectomy and left neck lymph node dissection. A final histopathological examination revealed minimally invasive follicular carcinoma.
Positron emission tomography–computed tomography (PET/CT) has been proposed as an imaging tool for malignancy risk stratification of Bethesda III and IV nodules with the potential of reducing futile thyroidectomy [42]. A visual assessment involves detecting focal ^18^F fluorodeoxyglucose ([^18^F]FDG) uptake within the thyroid at a level that is higher than the background. Several studies have shown that visual assessment of [^18^F]FDG uptake on [^18^F] FDG-PET/CT has high sensitivity and a high NPV when evaluating indeterminate thyroid nodules larger than 1 cm [43,44]. De Koster et al. [45] reported in a recent double-blinded, randomized controlled multicenter trial that [^18^F]FDG-PET/CT can reduce unnecessary surgery by 40% in patients with indeterminate thyroid nodules larger than 1 cm. It is noteworthy that Hürthle cell nodules may show FDG uptake regardless of their histopathologic characteristics, potentially confounding analyses using standardized uptake value (SUV)-based cut-offs [42]. Aside from direct visual assessment, PET/CT predictive models using quantitative metrics (e.g., maximum SUV [SUVmax]) have been reported to help rule out malignancy in Bethesda III and IV thyroid nodules [46]. That study found that a SUVmax threshold of 2.1 can reliably differentiated between benign and malignant non-oncocytic nodules with an NPV of 94.1%. In contrast, a much higher SUVmax threshold of 5.2 should be applied to optimize rule-out ability in Hürthle cell nodules, with an NPV of 100% [46]. A multicenter study demonstrated that molecular testing and [^18^F]FDG-PET/CT individually provided high NPVs (91% and 95%, respectively) for indeterminate thyroid nodules, but with varying sensitivity and specificity; thus, combining [^18^F]FDG-PET/CT and molecular testing increased the accuracy for excluding malignancy [47]. In summary, [^18^F]FDG-PET/CT can rule out malignancy in indeterminate thyroid nodules with a reasonable level of confidence when FDG uptake is negative.
To conclude, radioisotope scans with supplemental semi-quantitative analyses appear to be an accurate and cost-effective method for evaluating cytologically indeterminate thyroid nodules [42,48]. However, [^18^F]FDG-PET/CT is less effective in oncocytic indeterminate thyroid nodules [47]. Additionally, radioisotope imaging carries the risk of ionizing radiation, with an effective radiation dose of over 20 mSv in whole-body [^18^F]FDG-PET/CT [49]. Current guidelines do not recommend the routine use of these imaging methods for evaluating thyroid nodules [7,8,50].
Several studies have evaluated the effectiveness of repeat FNA for Bethesda III and IV nodules [51-54]. The Bethesda category is downgraded on repeat FNA cytology in approximately 7.4% to 55.2% of cases [52,55], while approximately 10% to 20% remain in the same Bethesda category and about 9% to 20% of Bethesda III nodules are upgraded into a more definitive category of Bethesda V or VI [51,52]. A change in the Bethesda category—either downgrading the nodule to benign or upgrading it to a malignant category—enables a more definitive management plan (conservative follow-up or total thyroidectomy) to be employed. The optimal timing for repeat FNA remains a topic of debate. While it was initially recommended to wait at least three months after the initial aspiration to avoid misdiagnosis due to possible reparative or reactive changes, recent studies suggest that a 3-month waiting period may not be necessary [5].
CNB offers the advantage of obtaining a larger tissue sample than FNA, which reduces the incidence of nondiagnostic results due to insufficient follicular cells and provides additional architectural and histological information beneath the capsule [56]. Moreover, a modified US-guided biopsy technique that includes the nodule, capsular portion, and surrounding parenchyma has been shown to yield higher diagnostic accuracy for indeterminate nodules (Fig. 2) [57]. A systematic review and meta-analysis revealed that CNB is a safe procedure, with an overall complication rate of 1.11%, a major complication rate of 0.06%, and a minor complication rate of 1.08% [58]. Another systematic review and meta-analysis indicated that the inconclusive rate for CNB was 8.0% (95% CI, 4.4% to 11.5%), in contrast to a 40.2% inconclusive rate for FNA (95% CI, 25.1% to 55.3%) [59]. Joo et al. [60] reported that CNB was more effective than repeat FNA in avoiding diagnostic surgery for nodules initially diagnosed as Bethesda III. The Korean Society of Thyroid Radiology (KSThR) has recommended CNB as a viable alternative to FNA for indeterminate thyroid nodules [56].
Fig. 2. Schematic illustration of conventional and modified core needle biopsy (CNB) techniques.In the conventional CNB technique, the specimen notch is entirely embedded in the nodular portion (A), while in the modified CNB technique, the specimen notch is centered in the capsule, thus the tissue core includes the nodular portion, capsule, and adjacent thyroid parenchyma (B) [57].
Molecular tests using mutational analysis and/or gene expression have been proposed as an ancillary tool for risk stratification in Bethesda III and IV thyroid nodules. They may play a role in helping avoid futile surgery for benign nodules and distinguishing higher-risk nodules that may benefit from a total thyroidectomy in advance [61,62].
Several genetic alterations associated with thyroid cancer have been discovered, such as point mutations in the BRAF and RAS genes in papillary thyroid cancer (PTC), as well as point mutations in the RAS gene and rearrangements of the PPARG/PAX8 genes in follicular thyroid cancer [61]. Various molecular tests have been proposed over the years, with reported NPVs and positive predictive values (PPVs) ranging from 56% to 100% and from 19% to 100%, respectively [63,64]. The most widely used tests include Thyroseq and the Afirma Genomic Sequencing Classifier (GSC), while other tests such as ThyGenX/ThyraMIR also become commercially available (Table 1) [65]. The Thyroseq has evolved from version 1 to the latest version 3, analyzing 112 thyroid cancer-related genes in next-generation sequencing platforms [64]. A prospective multicenter study utilizing the Thyroseq version 3 for Bethesda III and IV nodules reported a sensitivity of 94%, specificity of 82%, NPV of 97%, and PPV of 66%, leading to a 61% decrease in diagnostic surgery [66]. The earlier Afirma Gene Expressing Classifier test exhibited a sensitivity of 92% and a specificity of 52% for malignancy, with the NPV for Bethesda III and IV nodules diagnoses being 95% and 94%, respectively [68]. The updated version of the Afirma GSC is an RNA sequencing-based test, including 12 classifiers composed of 10,196 genes and seven additional components, aiming to help differentiate Hürthle cell neoplasms from benign Hürthle cell changes and identify medullary thyroid cancer or parathyroid lesions [64]. A multicenter validation study involving 183 patients showed a sensitivity of 91%, a specificity of 68%, an NPV of 96%, and a PPV of 47% with a 24% cancer prevalence [67].
A recent randomized clinical trial compared the diagnostic performance of Thyroseq v3. and the Afirma GSC and showed that both tests exhibited high specificity, allowing 49% of patients with indeterminate nodules to avoid unnecessary surgery; no significant difference in diagnostic performance was demonstrated [69]. In summary, these molecular tests provide a high NPV to rule out the likelihood of malignancy in Bethesda III and IV nodules.
The major limitation of molecular tests, nevertheless, is their relatively high cost. Several studies performed a cost-effectiveness analysis of molecular tests versus diagnostic surgery and reported variable results [70,71]. A study showed that molecular testing resulted in a 20% reduction in the use of diagnostic lobectomy and a corresponding increase in initial total thyroidectomy, thereby reducing the overall cost since performing upfront total thyroidectomy costs less than diagnostic lobectomy with completion thyroidectomy, even considering the added cost of molecular testing [72]. However, there is wide variation in the costs of molecular tests and surgery across different countries. In countries where surgical cost is lowered by national health insurance, the cost-effectiveness of molecular testing becomes less apparent [73]. A recent retrospective cross-sectional study analyzed molecular testing in 8,960 FNA samples from 2017 to 2021 [74]. The study found that wider adoption of molecular testing may have unintentionally led to an increase in Bethesda III lesions and a decrease in the PPV from 85% to 50% [74]. Therefore, physicians using molecular testing should be aware of the potential outcomes for better patient counseling.
Hemithyroidectomy remains the gold standard for achieving a definitive diagnosis of indeterminate thyroid nodules [7,75]. Most current guidelines recommend surgery for Bethesda IV nodules, while active surveillance can be an option for Bethesda III nodules in the absence of worrisome clinical and US factors [7].
The extent of surgery remains debatable. Generally, hemithyroidectomy is sufficient for diagnostic purposes, while total thyroidectomy may be justified in specific circumstances such as bilateral lesions, large lesions, a family history of thyroid cancer, or a history of neck radiation [75]. However, hemithyroidectomy is rarely the preferred procedure without a definitive preoperative diagnosis—it is either unnecessary for a benign lesion or inadequate for a malignant lesion. Schneider et al. [76] reported in a single-center database analysis of 639 patients that nearly 30% of patients with indeterminate thyroid nodules had an inappropriate extent of thyroidectomy from an oncologic point of view. A retrospective analysis involving 3,821 patients reported that up to 60% of patients with indeterminate thyroid nodules had been over- or under-treated at initial surgery [77]. Another retrospective multicenter study revealed that nearly 60% of patients with cytologically indeterminate thyroid nodules who underwent surgery had benign conditions, suggesting the possibility of unnecessary surgical interventions [78].
Prophylactic central neck lymph node dissection may provide survival benefits in patients with PTC, whereas its use in patients with Bethesda III or IV nodules is not recommended [79]. Furthermore, guidelines do not recommend the use of intraoperative frozen sections for indeterminate lesions, since this method is often nonspecific and cannot reliably distinguish between benign and malignant lesions [75].
Thermal ablation techniques include laser ablation (LA), RFA, and microwave ablation (MWA). These methods share the fundamental principle of inducing coagulative tissue necrosis through heat energy, which is generated by LA fibers, radiofrequency electrode needles or microwave antennas [80,81]. Thermal ablation of thyroid nodules is a safe and effective minimally invasive technique that has been adopted in the treatment of benign thyroid nodules, nodal metastasis of PTC, and papillary thyroid microcarcinoma [80]. The use of thermal ablation on Bethesda III and IV thyroid nodules, however, remains debated. Nonetheless, it has provided a treatment option for those who are ineligible or unwilling to undergo surgery.
Dobrinja et al. [23] first reported RFA of six patients with Bethesda III and IV nodules; two of which (33%) regrew as early as 6 months after RFA and ultimately required surgery. The definitive histopathology showed minimally invasive follicular carcinoma and follicular neoplasm with indeterminate malignant behavior [23]. Ha et al. [18] reported RFA of 10 patients with small (<2 cm) follicular neoplasms in 2017, demonstrating the safety and efficacy of this alternative treatment. No recurrence was found in the ablated zone in the 5-year follow-up and an average of 99.5% volume reduction rate was achieved [18]. Several studies have since reported RFA of Bethesda III and IV thyroid nodules (Table 2) [19-22]. Lin et al. [19] reported RFA for 22 patients with follicular neoplasms, showing volume reduction rate at 6-12 months after RFA of 73.3%±17.7%. Of note, PET/CT was used in this study to select low-SUV (SUVmax <5) follicular neoplasms for RFA [19]. Issa et al. [20] analyzed RFA of 53 Bethesda III or Bethesda IV thyroid nodules and concluded that the results were comparable to that of benign thyroid nodules in terms of the volume reduction rate, operative success, and nodular regrowth rate. Chiang et al. [21] reported RFA for 30 Bethesda III nodules with volume reduction rate of 77.9% at 6 months and 87.4% at 12 months. In this study, aside from repeat FNA cytology, the US RSS by ACR-TIRADS was also adopted for patient selection [21]. A recent prospective observational study of RFA in 62 small (≤2 cm) Bethesda IV thyroid nodules showed an average volume reduction rate of 82.0% at the 12-month follow-up, with high vascularity and chronic thyroiditis adversely impacting the complete absorption of the ablated nodule [22]. Except for the two cases described by Dobrinja et al. [23], none of these studies reported malignant transformation of ablated thyroid nodules or lymph node metastasis after RFA.
The limitations of these studies include relatively small sample sizes, single-center designs, and a relative lack of long-term follow-up. More large-scale prospective studies are needed in the future.
LA typically involves the use of a 21G biopsy needle to introduce an optic fiber for energy delivery [80]. It emerged in the 2000s as a novel treatment for benign thyroid nodules and has since gained popularity [82]. However, several prospective randomized trials have shown that RFA achieved a significantly better nodule volume reduction at 6 and 12 months than LA [83,84]. A systematic review and meta-analysis also demonstrated the superiority of RFA to LA in reducing benign solid thyroid nodule volume [85]. To date, the use of LA in treating thyroid nodules with indeterminate cytology has not been reported.
The efficacy of MWA in treating Bethesda III and IV nodules is less commonly reported compared with RFA. A recent study compared the outcomes, complications, and costs of MWA and thyroidectomy [86]. A total of 130 patients with 132 Bethesda IV thyroid nodules were retrospectively reviewed, with 46 patients receiving MWA group and 84 patients undergoing surgery. The 12-month nodule volume reduction rate of patients in the MWA group was 85.01%±10.86%. No local recurrence, nodal, or distant metastasis was found in the MWA group within the 12-month follow-up period. Compared with the surgery group, the MWA group presented significantly better cost-effectiveness (shorter treatment time, length of stay, and cost) and fewer complications [86]. However, the selection criteria between surgery and MWA were not clearly presented, probably because of the retrospective nature of the study, and the risk of malignancy in the surgery group was nonnegligible (9% borderline tumor and 44% thyroid malignancy). In addition, the follow-up time was only 12 months in the MWA group. Thus, further studies with longer follow-up times are needed to show the long-term efficacy of MWA on Bethesda IV nodules.
The current guidelines from the international societies do not recommend thermal ablation as first-line management for Bethesda III and IV thyroid nodules due to insufficient evidence of treatment benefit [7,17]. In an early small-scale report of RFA for Bethesda III and IV nodules, two out of six nodules eventually regrew and required surgery [23]. Although RFA did not seem to affect the subsequent treatment and postoperative pathology, it is likely to delay surgery [23]. Whether ablation speeds up the malignant transformation from follicular neoplasms into follicular carcinoma remains unclear, although previous reports on benign thyroid nodules have demonstrated no carcinogenic effect or tissue damage on the normal thyroid tissue adjacent to the RFA-ablated zone [87].
A recent study addressed the issue of delayed cancer diagnosis in nodules initially treated as benign with RFA, despite two prior benign diagnoses on FNA or CNB [88]. Among the 148 nodules studied, 36 (24.3%) showed regrowth, and seven (19.4%) were eventually confirmed as malignant following surgical intervention. Specifically, six nodules were identified as follicular carcinoma, while one was diagnosed as a follicular variant of PTC. The study revealed that the median volume of nodules before RFA was significantly larger in malignant cases than in benign cases (P=0.04), and the median volume reduction rate was significantly lower in malignant nodules (P=0.01) compared to benign ones. Based on these findings, the authors concluded that large symptomatic benign thyroid nodules showing regrowth or insufficient volume reduction after RFA may harbor malignant potential.
In thermal ablation of PTC, the ablation zone is recommended to extend 3-5 mm beyond the tumor edge, to prevent a marginal residue and confirm complete ablation [89]. Given that Bethesda III and IV thyroid nodules harbor higher malignant potential than Bethesda II thyroid nodules, a wider ablation zone beyond the tumor edge may help to ensure a safe margin and reduce the risk of recurrence. Various advanced techniques, such as artery-first ablation, marginal venous ablation, hydrodissection, and the moving-shot technique, have been developed to further reduce the likelihood of marginal regrowth while ensuring patient safety [90].
Unlike surgical excision, thermal ablation lacks the definitive histopathologic diagnosis; therefore, the risk of malignancy cannot be entirely ruled out. Adopting a shared decision-making approach between the physician and the patient, as well as additional non- or minimally invasive tests (e.g., US RSS, molecular testing, or radioisotope imaging) may aid in better patient selection for thermal ablation. In cases where a follicular neoplasm is suspected, especially with larger nodules, it is crucial to thoroughly inform the patient about the potential risk of malignancy following thermal ablation and the necessity for ongoing surveillance. Further large-scale studies with long-term follow-up may help establish the safety and efficacy of thermal ablation.
The management of Bethesda III and IV thyroid nodules can be challenging. It is important to strike a balance between organ preservation and early detection of thyroid cancer. In today's era of precision medicine, various advanced diagnostic tools, such as molecular testing and radioisotope imaging, can help reduce the need for lobectomy. US-guided thermal ablation is a safe and effective treatment option for patients with Bethesda III and IV thyroid nodules who are not suitable for surgery or refuse it. As more high-quality research evidence is published, thermal ablation is expected to become an increasingly popular method for managing these lesions in the future.