Abstract

Background

Ultrasound-guided thermal ablation plays an important role in the management of thyroid disease. The objective of this study was to evaluate the feasibility, efficacy, and safety of thermal ablation for patients with solitary T1bN0M0 papillary thyroid carcinoma (PTC) who are ineligible for or unwilling to undergo surgery.

Materials and Methods

Data pertaining to 172 patients (38 males and 134 females) who received thermal ablation therapy at 12 hospitals between April 2015 and March 2020 were retrospectively analyzed. The mean duration of follow-up was 24.9 ± 14.1 months (range, 12–60). The technical feasibility, technical success, efficacy, and safety of treatment were analyzed. Post ablation tumor size at various time points was compared with pre-ablation measurement.

Results

All patients selected for thermal ablation received enlarged ablation, according to contrast-enhanced ultrasound post ablation. The maximum diameter and volume of ablation zone at 6, 12, 18, 24, 36, and 48 months post ablation were significantly smaller than those recorded pre-ablation (P < 0.05 for all). At the most recent follow-up, 106 (61.6%) tumors had completely disappeared. The rate of lymph node metastasis was 0.6% (1/172) and the incidence of new tumors was 1.2% (2/172). The overall complication rate was 5.2% (9/172) (major complications: 4.6% [8/172]; minor complications: 0.6% [1/172]). All major complications were relieved within 4 months post  ablation.

Conclusion

Thermal ablation may be a feasible, effective, and safe treatment option for patients with solitary T1bN0M0 PTC who are ineligible for or unwilling to undergo surgery. It may provide a novel treatment option for selected patients.

Thyroid carcinoma is currently the 5^th most common malignancy in women worldwide, accounting for 5.1% of the estimated total cancer burden among women (1). Papillary thyroid carcinoma (PTC) is the most common sub-type of thyroid carcinoma; it is associated with a favorable prognosis and a low mortality rate (2, 3). Although surgery is the standard treatment for PTC, there is still much disagreement pertaining to the management of PTC (4, 5). Papillary thyroid carcinoma often represents a very low-risk lesion with an indolent course; therefore, surgical thyroidectomy may be a very aggressive therapeutic choice for some patients (6, 7). Further, some patients are ineligible for surgery, while others may be unwilling to undergo surgery for physical or cosmetic reasons. Therefore, exploration of other treatment options for PTC is a key imperative.

As a new, minimally invasive treatment modality, ultrasound (US)-guided thermal ablation (eg, microwave ablation [MWA] and radiofrequency ablation [RFA]) may play an important role in the management of thyroid disease in contemporary practice. The 2017 Thyroid Radiofrequency Ablation Guidelines and the first Italian opinion statement suggest that RFA can be used as an alternative to surgery in patients with benign thyroid nodules and in selected patients with recurrent thyroid cancer (8, 9). Some studies have reported favorable outcomes of thermal ablation in patients with T1a PTC (10–14). However, few studies have investigated the outcomes of thermal ablation treatment in patients with T1b PTC (15–17). Therefore, the purpose of this multicenter study was to evaluate the feasibility, efficacy, and safety of thermal ablation treatment for patients with solitary T1bN0M0 PTC who are ineligible for or unwilling to undergo surgery.

Materials and Methods

This was a retrospective study of patients treated at 12 hospitals in China. The study protocol was approved by the ethics committees of all the participating hospitals. The requirement for informed consent of patients for publication of data was waived. Prior to the ablation procedure, informed consent was obtained from all patients for the procedure. In clinical practice, surgery is initially recommended for the treatment of PTC. However, after being informed of the risk and advantages of ablation, patients who were ineligible for or unwilling to undergo surgery chose MWA or RFA treatment.

Patients

From April 2015 to March 2020, 172 patients who received MWA or RFA treatment for PTC at 12 hospitals were included in this study. Among these, 123 patients were treated with MWA and 49 patients were treated with RFA.

The inclusion criteria were: (1) patients with pathologically confirmed PTC; (2) unifocal T1bN0M0 PTC (including patients with tumors located adjacent to the recurrent laryngeal nerve or trachea); (3) patients with no extrathyroidal extension; (4) patients with no history of treatment for PTC; (5) patients who were ineligible for or unwilling to undergo surgery; and (6) postablation follow-up of ≥12 months. The exclusion criteria were: (1) a tumor located in the isthmus of thyroid; (2) children or pregnant women; (3) patients with suspected lymph node metastasis (LNM) preablation; (4) patients for whom complete follow-up data were not available; (5) patients with a serious bleeding tendency; and (6) patients with contraindications for the use of an US contrast agent.

Preablation assessment

Prior to ablation, all patients underwent high-frequency US examination of the neck, computed tomography (CT) of the neck and lung, US-guided fine-needle aspiration (FNA) or core-needle biopsy (CNB), and laboratory tests. The size (including 3 meridians) and location of the tumor were recorded by US. Specimens were sent for cytological or histological pathology and BRAF^V600E mutation tests. Laboratory tests included the measurement of thyroid function (serum triiodothyronine [T3], serum free thyroxine [fT4], serum thyrotropin [TSH], serum thyroglobulin [Tg] or antithyroglobulin antibody [Tg-Ab]), complete blood count, and blood coagulation battery).

All US examinations and FNA biopsies were carried out by radiologists who had more than 3 years of experience in US examination. Contrast-enhanced US (CEUS) and ablation were carried out by radiologists who had more than 3 years of experience in thyroid ablation.

Ablation equipment

For MWA, the Intelligent Basic Type Microwave Tumor Ablation System (Nanjing ECO Microwave System, Nanjing, China) or the KY-2000 microwave system (Kangyou Medical, Nanjing, China) were used in the study. A 16-gauge (G) or 17-G, Teflon-coated, internal-cooled microwave antenna with a 0.3- or 0.5-cm active tip and a 10- or 15-cm shaft length were applied, depending on the size and location of the targeted tumor. For RFA, the Cooltip Radiofrequency Ablation System (Covidien, Shanghai, China) was used in the study. A 17-G, monopolar, modified, internal-cooled radiofrequency electrode with a 0.5- or 0.7-cm active tip and a 15-cm shaft length was applied, depending on the size and location of the targeted tumor.

Ablation procedure

Patients were placed supine and their necks were fully exposed. The ablation site was routinely sterilized and draped with sterile towels. Prior to ablation, CEUS examination was performed to evaluate the enhancement pattern of the tumor. A second-generation US contrast agent SonoVue (sulfur hexafluoride microbubbles; Bracco, Milan, Italy) was used in the study. The US contrast agents are usually injected through a 20-G cannula in the median cubital vein (usually in the left arm) followed by a 5 to 10 mL sterile saline flush (18). Thereafter, local anesthesia (1% lidocaine) was administered at the designated ablation site and hydrodissection techniques were used (19). An 18-G core needle (Hakko Medical, Nagano-Ken, Japan) was inserted along the thyroid capsule into the area between the target tumor and the adjacent critical structures; for example, fluid was injected into the area between the tumor and the trachea or the recurrent laryngeal nerve (RLN) to keep them far from the tumor in order to avoid heat injury during ablation. The isolation distance was at least 5 mm during ablation and fluid was continuously and slowly injected to maintain the safe distance, if necessary. For the ablation, a microwave antenna with a 0.3- or 0.5-cm tip or a radiofrequency electrode with 0.5- or 0.7-cm active tip were used. The choice between MWA and RFA was based on the individual preference of the operator. The typical power output for MWA and RFA was 30 to 40 W and 30 to 60 W, respectively. The moving-shot or fixed-applicator technique was applied based on tumor characteristics. The ablation was terminated when a transient hyperechoic echotexture covered the tumor. Postablation CEUS was used to evaluate the ablation effect. The ablation was considered complete if unenhanced ablation zone on CEUS covered the tumor and extended beyond the margins of the tumor for at least 1 to 2 mm. An additional ablation was immediately undertaken in case of detection of an enhancement area within the tumor or if the extension beyond the tumor margin was not enough. Representative images of preablation US and pre- and postablation CEUS images illustrating the ablation process are shown in Fig. 1.

 

Postablation follow-up

Postablation, US examination was used to observe the contraction of the vocal cords to determine any injury to the RLN (20). All patients were followed up at 1, 3, 6, or 12 months for the 1^st year, every 6 months for the 2^nd year, and every 12 months thereafter. Laboratory tests and US examination were performed at each follow-up. Computed tomography of the neck and lung was performed every 12 months postablation. Contrast-enhanced US and FNA were carried out if tumor recurrence or LNM was suspected. The tumor volume was calculated using the following equation: V = πabc/6, where V is the volume; a is the maximum diameter (MD), and b and c are the other 2 perpendicular diameters (21). The percentage volume reduction was calculated as follows: volume reduction ratio (VRR) = ([initial volume – final volume] × 100) / initial volume.

Definitions

Technical feasibility was defined as the ability to target the tumor and perform the ablation as preoperatively planned. Technical success was defined as the complete absence of enhancement on CEUS at the end of every procedure. The treatment efficacy was evaluated using several parameters: changes in the size and volume of the tumor, disappearance rate of the tumor, and disease progression (including local recurrence, any new tumors, LNM, distant metastasis, or death due to PTC). The safety of treatment was evaluated using a rate of complications. Complications were recorded using the standard of the Society of Interventional Radiology (22).

Statistical analysis

The technical feasibility, technical success, efficacy, and safety of treatment were analyzed. Descriptive statistics are presented as the mean ± standard deviation (SD) or median for continuous variables, and as frequency (percentage) for categorical variables. A paired t-test was used to compare changes in thyroid function, size, and volume of tumor between pre- and postablation. All statistical analyses were conducted using the SPSS software package (SPSS Statistics, version 26.0; SPSS Inc., Chicago, Illinois); P-values < 0.05 were considered indicative of statistical significance.

Results

Demographic characteristics

The demographic characteristics of the study population (age range [mean ± SD] 18–78 [45.9 ± 12.6] years) are summarized in Table 1. A total of 124 (72.1%) patients refused surgery due to cosmetic reasons and 48 (27.9%) patients were ineligible for surgery. Among these, 16 patients had renal failure, 13 patients had severe diabetes, 2 patients had severe anemia, 9 patients had other malignancies, and 8 patients had asthma. The mean follow-up period was 24.9 ± 14.1 months (range, 12–60); 78, 29, 26, 13, 24, and 2 patients were followed-up for more than 12, 18, 24, 36, 48, and 60 months, respectively. Thyroid function at 1 month postablation was not significantly different from the preablation level (P > 0.05 for all).

 

There were no differences between the MWA and RFA groups with respect to age (P = 0.83), sex (P = 0.12), or MD (P = 0.57) of the tumors (Table 1). There were no differences between the 2 groups with respect to tumor disappearance or complication rates (P = 0.15 and P = 0.96, respectively). There were no differences between the BRAF^V600E mutation and BRAF^V600E negative groups with respect to disease progression (P > 0 .99).

Tumor characteristics

Eighty-four (48.8%) tumors were located in the left lobe and 88 (51.2%) tumors in the right lobe. The preablation MD of tumors ranged from 11 to 20 mm (mean 13.3 mm). The volume of the tumors ranged from 201 to 3391 mm³ (mean: 810 mm³). The ablation time of tumors ranged from 52 to 643 seconds (mean: 220 seconds). The number of target tumors that exhibited a hyper-, iso- and hypoenhancement pattern on preablation CEUS were 44 (25.6%), 24 (14.0%), and 104 (60.5%), respectively.

Assessment of technical feasibility and success

All tumors in our study were correctly targeted and ablation was performed successfully with MWA or RFA, as per the preoperative plan. The complete absence of enhancement on CEUS was finally achieved in all target tumors at the end of ablation. The technical feasibility and success rate of thermal ablation in our cohort were both 100% (172/172).

Assessment of treatment efficacy

The changes in the MD, volume, and VRR of the tumors at pre- and postablation are shown in Table 2 and Fig. 2. Due to expanding ablation, the MD and volume of ablation zone at 1 month postablation were significantly larger than those of the original tumor recorded preablation (P < 0.05 for both). The MD and volume of ablation zone at 3 months postablation were not significantly different from those of the original tumor recorded preablation (P = 0.13 and P = 0.46, respectively). The MD and volume of ablation zone, at 6, 12, 18, 24, 36, and 48 months postablation were significantly smaller than those of the original tumor recorded preablation (P < 0.05 for all). The VRR changed from negative to positive at 6 months postablation.

 

 

At the most recent follow-up, a total of 106 (61.6%) tumors had completely disappeared on US. Nine tumors had disappeared at 6 months, 59 had disappeared at 12 months, 27 had disappeared at 18 months, and 11 had disappeared at 24 months. The rate of LNM was 0.6% (1/172) and the incidence rate of a new tumor was 1.2% (2/172). There was no local recurrence or distant metastasis; none of the patients died of PTC during follow-up.

In this study, 3 patients developed disease progression after the 1^st treatment. The preprocedure tumor characteristics of patients who developed disease progression are shown in Table 3. One patient developed an additional new tumor (MD: 4 mm) in the contralateral thyroid lobe at 19 months postablation and underwent second ablation. Another patient developed an additional new LNM in level IV of the ipsilateral neck at 13 months postablation and underwent surgery. Another patient developed an additional new tumor (MD: 3 mm) in the ipsilateral thyroid lobe at 24 months postablation and underwent second ablation. At the end of follow-up, none of the 3 patients showed any signs of disease progression again after the 2^nd treatment.

 

Assessment of treatment safety

The overall complication rate in our cohort was 5.2% (9/172), the major complication rate was 4.6% (8/172), and the minor complication rate was 0.6% (1/172). The characteristics of 8 patients who developed hoarseness postablation are shown in Table 4. Hoarseness of the voice occurred in 8 patients as a major complication. All symptoms were relieved within 4 months without any specific therapy. Of these 8 patients, 2 patients returned to normal 1 month postablation, 1 patient returned in 2 months, 2 patients returned in 3 months, and 3 patients returned in 4 months. High fever occurred in 1 patient postablation as a minor complication. The fever was relieved on the next day. None of those complications were life-threatening, and all patients recovered without any sequelae. One patient died of a traffic accident at 12 months postablation.

 

Discussion

This multicenter study suggests that thermal ablation may be a feasible, effective, and safe treatment for patients with solitary T1bN0M0 PTC who are ineligible for or unwilling to undergo surgery. Over a mean follow-up period of 24.9 months, 61.6% of tumors had completely disappeared. The rate of LNM was 0.6% and the rate of new tumors was 1.2%. The overall complication rate was 5.2%; however, there was no life-threatening complication.

All tumors in the present study were successfully ablated as per the preoperative plan. The technical feasibility and success rate of thermal ablation in our cohort were both 100%. In a meta-analysis of 1187 patients with papillary thyroid microcarcinoma, the disappearance rate of tumor was found to vary from 34% to 91% postablation (23). We believe that the disappearance rate of the tumor is related to the size and characteristics of the tumor and the follow-up period; therefore, there is certain variability in the results of different studies. In the meta-analysis, the rate of postablation LNM was found to vary from 0.6% to 2.0% (23). In a study by Xiao et al (15), the rate of LNM after RFA was 1.5% in patients with T1b PTC during a mean follow-up period of 20.5 months. In addition, in many studies, the local recurrence rate postablation was below 0.5% (12, 23, 24). In our large multicenter study, none of the patients developed local recurrence during follow-up. Therefore, our study demonstrates that thermal ablation is a feasible and effective option for treating solitary T1bN0M0 PTC patients who are ineligible for or unwilling to undergo surgery.

In a meta-analysis of 12 studies about T1a PTC, the pooled incidence of complications post-MWA and post-RFA was 6.0% and 1.7%, respectively (23). The incidence rates of voice hoarseness post-MWA and post-RFA were 4.4% and 1.8%, respectively. In another meta-analysis of 10 studies about locally recurrent thyroid cancer, the pooled incidence of complications post-RFA was 5.8% (25). In another study on benign thyroid nodules, the overall complication and voice hoarseness rates post-RFA were 3.3% and 1.0%, respectively (26). The overall complication rate and voice hoarseness rate in our study were 5.2% and 4.6%, respectively. However, none of the patients developed permanent hoarseness. In addition, in some previous studies about ablation, none of the patients developed transient or permanent hypothyroidism postablation (14, 17, 24, 27, 28). Similarly, none of patients in our study developed hypothyroidism. Therefore, our results demonstrate that thermal ablation is a safe option for the treatment of solitary T1bN0M0 PTC patients who are ineligible for or unwilling to undergo surgery.

The lack of local recurrence postablation and the low complication rate in the present study was likely attributable to several technical innovations. On one hand, the margin of ablation extended at least 1 to 2 mm from the tumor to obtain a safety margin for the prevention of local recurrence; this strategy has been successfully employed in the context of hepatocellular carcinoma ablation (29). On the other hand, the hydrodissection technique helps safely isolate the tumor from the anatomically contiguous critical structures, thus preventing heat injury. According to our experience, continuous and slow injection of fluid is necessary and helps maintain a safe distance to avoid heat injury during ablation.

Some limitations of this study need to be acknowledged. First, PTC diagnosis was based on cytopathology or histopathology, and failed to obtain the complete pathology of tumors. Therefore, the pathological type and risk status of PTC cannot be accurately evaluated. Secondly, postablation histological examination of tumors was not performed; therefore, the persistence of low-level residual cancer cannot be ruled out. Third, the mean follow-up period in this study was 25 months; considering the prognosis of PTC, the follow-up period was relatively short.

In conclusion, this multicenter study demonstrated that thermal ablation may be a feasible, effective, and safe treatment option for patients with solitary T1bN0M0 PTC who are ineligible for or unwilling to undergo surgery.