Thermal ablation for papillary thyroid carcinoma in the isthmus: a systematic review and meta-analysis

Introduction

In 2020, thyroid cancer (TC) was the ninth most common cancer in the world. One in every 20 cancers diagnosed among women was TC (1). In the United States, TC accounted for approximately 44,000 new cancer diagnoses in 2022, representing 2.3% of the total number of cancer cases reported that year (2). From 2005 to 2015, the age-standardized incidence rate of TC in China increased from 3.21/100,000 to 9.61/100,000, representing an annual percentage change of 12.4% (3). Compared to the incidence rate, the mortality rate of TC was significantly lower, averaging approximately 0.5 deaths per 100,000 individuals annually (2).

Papillary thyroid carcinoma (PTC), representing approximately 80–90% of all thyroid malignancies, was regarded as the main reason for the continuous increase in the incidence of TC worldwide (4,5). This has been primarily attributed to the widespread adoption of routine screening modalities such as computed tomography (CT), magnetic resonance imaging (MRI), and neck ultrasonography, coupled with significant advancements in the detection and diagnostic techniques for incidentally discovered asymptomatic thyroid nodules (6-8).

A small proportion of PTC lesions occur in the isthmus, which connects both thyroid lobes and is adjacent to the trachea dorsally and strap muscles anteriorly. Papillary thyroid carcinoma in the isthmus (PTCI) was reported to account for 2.5–12.3% of all PTC case (9-11). Since PTCI is more likely to be associated with multifocal disease, lymph node metastasis (LNM), and capsule invasion, surgical procedure is suggested as the first-choice treatment for patients with PTCI (12,13). However, it has some shortcomings, including hypothyroidism, vocal cord paralysis and hypoparathyroidism. At the same time, it may cause psychological burden on patients and reduce their quality of life (14,15). The 2015 American Thyroid Association (ATA) guidelines recommended active surveillance (AS) as an alternative treatment for PTC to avoid unnecessary surgery (16), but patients may face problems such as tumor growth and local metastasis. Moreover, Nakamura et al. found that patients with AS had a significantly higher risk of developing anxiety and depression (15).

Currently, many studies have pointed out that thermal ablation (TA), including radiofrequency ablation (RFA), microwave ablation (MWA) and laser ablation (LA), is a safe and effective method for treating thyroid nodules and is recommended for clinical work (17-20). Although major guidelines have positioned TA as a potential option for selected PTC patients, no consensus has been reached regarding its application in PTCI cases (21,22). Reliable conclusions have not been established due to insufficient data and limited representation in clinical trials. Focusing specifically on PTCI, this study establishes the first comprehensive meta-analytic assessment of TA treatment outcomes, including efficacy benchmarks and complication rates. We present this article in accordance with the PRISMA reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-339/rc) (23).

Methods

The study protocol was prospectively registered with PROSPERO (Registration ID: CRD420250651356). A summary assessment of ethical adherence in the included studies was performed. It was noted that all studies stated that ethical approval had been obtained from their respective institutional review boards, and informed consent was procured from all participants (Table S1).

Literature search

We searched the studies published in PubMed, Embase and Cochrane Library from the establishment of the database to Jan 31, 2025. The search terms were as follows: (Thyroid Cancer, Papillary [mh] OR Papillary Thyroid Cancer [tiab] OR Papillary Thyroid Carcinoma [tiab] OR papillary thyroid microcarcinoma [tiab] OR Nonmedullary Thyroid Carcinoma [tiab]) AND (Radiofrequency ablation[tiab] OR RFA [tiab] OR Laser ablation [tiab] OR LA [tiab] OR Microwave ablation [tiab] OR MWA [tiab] OR Thermal ablation [tiab]), as detailed in Appendix 1. In addition, the references of relevant articles were reviewed to further include appropriate data.

Selection criteria

The inclusion criteria were (I) PTC definitively diagnosed via core needle biopsy (CNB) histological examination; (II) solitary PTC without evidence of LNM, distant metastasis (DM), or extrathyroidal extension (ETE); (III) PTC located in the isthmus on ultrasound examination; (IV) included the evaluation of the postoperative efficacy after TA.

The exclusion criteria were (I) case reports/series; (II) review articles/meta-analyses; (III) letters/abstracts/editorials; (IV) study included overlapping patient cohort.

Data collection and definition

The following data were collected in included studies: (I) general characteristics (first author, publication date, study period, study Design and method of ablation); (II) patient characteristics (number of patients, sex ratio, average age and follow-up time); (III) tumor characteristics (initial tumor diameter and initial tumor volume); (IV) postoperative characteristics {mean volume of the tumor [mean volume = (π/6) × a × b × c, where a, b, and c represent the maximal orthogonal diameters quantified from cross-sectional imaging], local tumor progression (LTP), locoregional recurrence (LRR), DM, postoperative complications}.

LTP was characterized by either of the following criteria: (I) histologically verified new or persistent PTC; (II) biopsy-confirmed metastasis to cervical lymph nodes. LRR referred to the emergence of malignant lesions within the thyroid bed, contralateral lobe, or regional lymph nodes that were identified more than six months after the initial procedure and confirmed via cytological examination or excision pathology (24). Suspected DM was investigated using CT, positron emission tomography (PET), or bone scintigraphy, depending on clinical indications.

Two researchers extracted the data independently. When opinions were inconsistent, the two researchers discussed and decided.

Literature quality assessment

The methodological quality of non-randomized studies were appraised using the Newcastle-Ottawa Scale (NOS), which assesses three domains, including selection of research objects, comparability, and outcome. Total scores were categorized per NOS protocols (Table S2).

The evaluation was conducted independently by two researchers. When opinions were inconsistent, we discussed with the third researcher to make a decision.

Statistical analyses

We used STATA 18.0 software for statistical analysis. The Higgins inconsistency index (I²) test was used to evaluate the heterogeneity of each study. For analyses with I²<50%, indicating low heterogeneity, we applied fixed-effects models to pool effect sizes. When I²≥50%, reflecting significant heterogeneity, random-effects models were employed. The threshold for statistical significance was set at P<0.05. To assess result robustness, sensitivity analyses were performed through sequential exclusion of individual studies. Finally, we conducted funnel plots and Egger’s test to evaluate potential publication bias.

Results

The initial search yielded a total of 939 published relevant articles from three databases. Following duplicate removal and sequential title/abstract screening, 81 studies met inclusion criteria for full-text evaluation. Then, 73 articles were excluded as they focused on patients with tumors located in the unilateral or bilateral lobes and 1 article was suspected of including overlapping cohorts. Finally, the data of 7 articles were included in the meta-analysis (Figure 1).

Figure 1 Flow diagram of the study selection process.

Characteristics of the included studies

Table 1 shows the basic characteristics of the seven studies included in the meta-analysis. There are 413 (73.75%) and 147 (26.25%) cases received RFA and MWA respectively, and the mean follow-up ranges were 25.0–31.1 and 17.0–36.1 months respectively. Four studies reported that the initial maximum diameter ranged from 5.6 to 8.0 mm and the initial mean volume ranged from 65.4 to 181.6 mm³ in the RFA group (24,25,27,30). Three studies reported that the initial maximum diameter ranged from 6.0 to 6.8 mm and the initial mean volume ranged from 85.9 to 140.0 mm³ in the MWA group (26,28,29) (Table 2). Moving-shot and hydro-dissection techniques were used during TA to minimize damage to the surrounding thyroid tissues and reduce complications. To avoid tumor recurrence or residue, TA was expanded at least 2–3 mm beyond the boundary of the initial tumor. All included studies employed standardized ultrasonographic protocols, integrating baseline grayscale ultrasound and contrast-enhanced ultrasound (CEUS), to assess technical success following TA (24-30) (Table 3).

Results of ablation

LTP

Technical feasibility and treatment success were reported in six studies, encompassing a cohort of 468 patients (24,25,27-30). All tumors were accurately targeted and completely ablated under ultrasound guidance in accordance with the preoperative plan, yielding a technical success rate of 100%. Furthermore, no LTP was observed during the follow-up period among these patients.

Tumor volume

The changes in tumor volume are shown in Figure 2. Owing to expanding ablation, the ablation zone volumes measured at 1- and 3-month follow-up imaging significantly exceeded pretreatment tumor volumes. However, the volume of the ablation zone at 12-, 18-month and the last follow-up after TA were smaller than that of the original tumor volume before TA.

Figure 2 Forest plots of the changes in tumor volume at (A) 1-, (B) 3-, (C) 6-, (D) 12-, (E) 18-month, (F) the last follow-up. CI, confidence interval; SD, standard deviation.

CDR

A total of six studies reported the CDR of PTCI lesions at the final follow-up, with a pooled CDR of 88.10% (95% confidence interval (CI): 66.20–99.87%). Due to significant heterogeneity (I²=95.73%, P<0.001), the CDR was further analyzed according to different ablation modalities. Subgroup analysis revealed that the overall CDR reached 98.51% (95% CI: 85.17–100.00%) in patients treated with RFA, while it was 52.89% (95% CI: 17.99–86.34%) in those who underwent MWA (Figure 3).

Figure 3 Forest plot of the complete disappearance rate. CI, confidence interval; MWA, microwave ablation; RFA, radiofrequency ablation.

LRR and DM

LRR included newly discovered PTC and LNM in this study. As shown in Figure 4, new primary tumors were observed in six patients [0.77% (95% CI: 0.04–2.06%)], whereas lymph node metastasis was documented in only one case [1/468 (95% CI: 0.00–0.56%)], located in level VI of the ipsilateral neck. Three patients underwent additional RFA successfully during the follow-up period. No patients were found to have DM.

Figure 4 Forest plots of locoregional recurrence (A) new tumor incidence, (B) lymph node metastasis. CI, confidence interval.

Complication rate

The combined rate of patients with complications was 0.89% (95% CI: 0.13–2.08%), including 1 coughing and 2 temporary hoarseness. There were no delayed complications during the follow-up period (Figure 5).

Figure 5 Forest plot of the complication rate. CI, confidence interval.

Sensitivity analysis

Sequential exclusion sensitivity testing revealed that none of the pooled results with 95% CI were significantly affected by any individual study. This consistency confirmed the reliability of our meta-analytic findings, as detailed in Figure S1.

Publication bias

To assess the validity of the meta-analysis conclusions, we performed Egger’s tests for the CDR and LRR. No significant publication bias was found (CDR: P=0.47, newly discovered PTC: P=0.44, LNM =0.84). With respect to the tumor volume changes, we postulated that the results were subject to publication bias at certain follow-up time points (e.g., 3-, 12-, 18-month and the last follow-up). This might be attributable to the limited number of included studies and their small sample sizes (Figure S2).

Discussion

PTCI denotes isthmus-confined papillary carcinoma, with tumor epicenter localized between the tracheal-parallel sagittal planes (extending anterolaterally to skin surface) that demarcate the 6±2 mm isthmic zone (31). To date, no clear guidelines on management of PTCI have been proposed. Jasim et al. (32) showed that PTC in the isthmus was more likely to present with LNM, capsular invasion, multifocality and extrathyroid dilatation than that in thyroid lobes. These features may be related to the small and thin shape of the isthmus, which is conducive to invading adjacent tissues. Most surgeons recommend treatments of total thyroidectomy and prophylactic central lymph node dissection for PTCI patients (33). However, other studies have put forward different viewpoints. Kwon et al. (34) showed that isthmus-confined PTC did not independently predict aggressive clinicopathological features, nor correlate with recurrence risk. Dan et al. (35) reported equivalent oncologic outcomes between isthmusectomy and total thyroidectomy in rigorously selected PTCI cases. This was in accordance with the research findings of Zhang et al. (36). Moreover, according to existing literature reports, any surgical method may lead to injury of adjacent organs or cause some complications, such as hypothyroidism, hypoparathyroidism, recurrent laryngeal nerve injury, and scar formation, etc., thereby affecting the patient’s quality of life (37,38).

TA as a minimally invasive treatment, may serve as a treatment option for selected patients with PTC who are unfit for or refuse surgery (17-19,21,22). Although a large number of published studies focused on patients with lobar PTC or papillary thyroid microcarcinoma (PTMC), they actually also included a small part of patients with PTCI. Due to the insufficient representativeness of samples in most published studies, no reliable conclusion has been reached regarding the treatment of patients with PTCI so far.

In this meta-analysis, the technical success rate of TA was 100% (468/468), with no evidence of LTP observed during the postoperative follow-up period. The volume of the ablation zone at 1 and 3 months follow-up after TA increased significantly compared with the original tumor volume. Analysis of the potential causes indicated that the short-term increase in lesion volume may be associated with the expanded ablation area and subsequent inflammatory response. Subsequently, as inflammation subsided and edema resolved, there was a significant reduction in the volume of the lesion. In a meta-analysis of TA for low-risk PTMC (n=11 studies), the pooled complete resolution rate was 57.6% (95% CI: 35.4–79.8%) with a 0.4% recurrence risk (95% CI: 0–1.1%) (39). Comparing the results of this meta-analysis with those of our systematic review, it was found that the efficacy of TA in the treatment of patients with PTCI appeared comparable to that observed in patients with lobar PTC. Subgroup analysis indicated that the CDR was significantly higher in patients with PTCI treated with RFA compared to those receiving MWA (92.51% vs. 52.89%). The relatively small proportion of patients treated with MWA in this study may have limited the accurate assessment of its efficacy. Furthermore, all procedures in the RFA group were performed by operators with over ten years of experience, whereas operators in the MWA group had comparatively less experience, which might also contribute to the observed difference in outcomes between the two modalities.

In terms of safety, the results of this meta-analysis showed that the pooled proportion of complications of PTCI was 0.89% (95% CI: 0.13–2.08%), which was consistent with previous studies (39). The complications may be related to local anesthesia and thermal reactions. Minimizing the occurrence of complications requires a detailed preoperative evaluation of the patient by an experienced physician prior to surgery (21). During the procedure, a variety of techniques can be used to prevent thermal damage, including moving shot techniques and hydrodissection. At the same time, Ultrasound-guided TA mandates real-time visualization of the needle trajectory, with continuous tip tracking to prevent collateral damage to critical structures (recurrent laryngeal nerve, trachea, major vessels).

There are still some limitations in this meta-analysis. Firstly, the included studies were all from China and mainly retrospective studies. This regional homogeneity may limit the generalizability of our findings to other populations with different genetic backgrounds, lifestyles, healthcare systems, and clinical practices. Meanwhile, the retrospective and observational nature of included studies introduced a lower level of evidence compared to prospective or randomized controlled designs, and unmeasured confounding biases cannot be ruled out. If high-quality randomized controlled trials from other countries could be included, the results would be more credible. Secondly, although most recurrences are detected within 2–3 years after initial treatment (40), the indolent biological nature of TC confers a potential for late recurrence. The follow-up durations reported in the literature were clustered within a 17- to 36-month period, representing only short- to mid-term outcomes, which may have resulted in false negative results when evaluating the recurrence rate of TC. Studies with longer follow-up periods and detailed time-to-event reporting are needed to verify reproducibility of the results. Finally, due to technical reasons, we were unable to retrieve all grey literature, including trial registers, conference abstracts and unpublished data, which may lead to publication bias.

Conclusions

In conclusion, this meta-analysis suggests the therapeutic viability of TA for PTCI, demonstrating compelling efficacy alongside a favorable safety profile. To address the current reliance on non-randomized evidence, future multicenter randomized controlled trials and comprehensive registry studies are imperative to refine treatment protocols and advance personalized therapeutic strategies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-339/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-339/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-339/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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