This study was approved by the ethics committee of the Chinese People’s Liberation Army General Hospital (S2019-211-01). Written informed consent was obtained from all patients prior to ultrasound-guided FNA, TA, and surgery. We reviewed the medical records of 61 patients who were diagnosed as Bethesda IV thyroid nodules by FNA in our department from January 2017 to December 2019, including 30 patients of ultrasound-guided TA treatment and 31 patients of surgical treatment ( Figure 1 ).

For the TA group, patients who fulfilled the following criteria were enrolled: (1) a solitary suspicious thyroid nodule was detected by ultrasound; (2) located in the thyroid gland and with no thyroid capsule contact; (3) no imaging evidence of extrathyroidal invasion, lymph node metastasis, or distant metastasis; (4) ultrasound-guided FNA confirming Bethesda IV cytology; (5) refusal of or ineligibility for surgery due to medical contraindications or other reasons; and (6) complete records and more than 12 months of follow-up.

For the surgery group, the inclusion criteria were as follows: (1) a solitary suspicious thyroid nodule was detected by ultrasound; (2) no imaging evidence of extrathyroidal invasion, lymph node metastasis, or distant metastasis; (3) ultrasound-guided FNA confirming Bethesda IV cytology; and (4) complete clinical data.

For the TA group and the surgery group, the exclusion criteria were: (1) suspicious cervical lymph node metastasis, (2) a history of head or neck irradiation, (3) severe diseases that cannot tolerate interventional and surgical treatment, and (4) a history of severe bleeding and coagulopathy.

Demographics information for each patient was obtained, and all patients underwent conventional ultrasound before treatment to evaluate nodule characteristics, including the diameters in three dimensions (transverse, longitudinal, and anteroposterior), volume, position, composition, echogenicity, shape, margin, and echogenic foci. The volume of each nodule was calculated as V =πabc/6 (where V is the volume; a, b and c are three diameters respectively). For all patients, Bethesda IV thyroid nodules was diagnosed based on cytology findings by ultrasound-guided FNA.

The ablation techniques include RFA and MWA, which are selected according to nodule characteristics, the relationship with adjacent organs, the patient’s own condition, and the physician’s experience. All TA procedures were performed by one physician with rich experience in thyroid ultrasound and interventional ultrasound, including initial diagnosis and preoperative evaluation. TA was performed in an outpatient ultrasound interventional room. Patients were placed in the supine position. Ultrasound was used to guide the positioning, and then conventional sterilization and sterile drapes were carried out. 1% lidocaine was used for local anesthesia. In order to protect normal structures, using the Hydrodissection technique, the tumor was separated from the critical structures by infusing a mixture of normal saline (11, 12). Before ablation, the approach route and the relationship between the tumor and vital cervical structures (i.e., the trachea, esophagus, recurrent laryngeal nerve, and blood vessels) should be evaluated. During ablation, ultrasound imaging was used for real-time monitoring to ascertain the correct position of the needle in the tumor.

The Siemens Acouson Sequoia 512 (Siemens, Mountain View, CA) scanner with a 6.0 MHz linear array transducer was used for guidance. The bipolar RFA generator (CelonLabPOWER; Olympus Surgical Technologies Europe, Hamburg, Germany) and a 18-gauge bipolar RF applicator with a 1.5cm active tip (CelonProSurge micro 100-T15; Olympus Surgical Technologies Europe) were used. Under the guidance of ultrasound, the electrode was inserted into the nodule. Ablation started at 3W of power, and the moving-shot technique was applied (13, 14). If there is no hyperechoic zone at the electrode tip within 5-10 seconds, the RF power was gradually increased. The procedure was not terminated until the whole tumor transformed into a transient hyperechoic zone, and the needle track was coagulated to prevent tumor cell seeding. The whole nodule with a 3mm safety margin was completely ablated to prevent marginal recurrence (15). If the tumor was close to thyroid capsule and less than 3mm, we ablated it together with capsule. At the end of each procedure, the ablation zone was evaluated by contrast-enhanced ultrasound; if residual enhancement was present, ablation was supplemented. All of the patients were discharged when their vital signs were stable after observation for 2 hours.

An MTI-5DT machine (Changcheng Microwave System Engineering Co., Ltd., Nanjing, Jiangsu Province, China) and XR-B1610W superficial organ ablation needle (17G, length: 100mm, diameter: 3mm) were used. When the ablation position was determined, the skin was incised 3mm subcutaneously, and the 17G-100 microwave needle was applied by moving-shot technique. After MWA was started the initial power was set to 25W. If there was no hyperechoic zone in the ablative area after 5-10s ablation with this power, the power was gradually increased (up to 35 W). Multifaceted and multipoint mobile ablation was performed until the lesion nodules were completely covered by hyperechogenic vaporization area. The ablation extent was 3 mm beyond the edge of the tumor to prevent marginal residual and recurrence. Contrast-enhanced ultrasound was performed immediately after ablation to evaluate the ablation area. If the ablation was incomplete, the ablation was supplemented; otherwise, the ablation was completed. After observation for 2 hours, patients were discharged with stable vital signs.

Surgery was performed by surgeons with rich experience in thyroid surgery. The decision to perform different surgical methods was made by individual surgeons and patients based on patient preferences in consultation with the surgeon.

After anesthesia was satisfied, the routine neck and shoulder surgery area was disinfected. An arc incision was taken to cut skin, subcutaneous tissue, and latissimus muscle. The thyroid gland was explored, the character of the nodule and the adjacent tissue was evaluated, and the resection was performed. The blood vessels were carefully separated and ligated. During the operation, the recurrent laryngeal nerve and parathyroid gland was protected. The tissue was cut and sent to frozen examination. Neurological function and bleeding were evaluated after surgery.

For the TA group, patients were followed up at 1, 3, 6, and 12 months after intervention, and every 6 months thereafter. The therapeutic effect was evaluated by ultrasound and volume of ablation was detected. The percentage reduction of the ablation area in volume was calculated as follows: Volume reduction ratio (VRR) = [(initial volume – final volume) × 100]/initial volume. Postoperative complications (voice hoarseness, hematoma, postoperative pain, incision infections, hypothyroidism, and hypocalcemia) (16), operation time, hospitalization time, blood loss, and incision length were recorded. Imaging was used to rule out the occurrence of distant metastasis and lymph node metastasis.

Using SPSS 23.0 software, continuous variables were expressed as mean ± SD, and t-test was used for comparison between groups; categorical data are presented as frequencies and percentages, and Pearson x² test or Fisher exact test was used for comparison between groups. Wilcoxon’s signed rank test was used to compare changes in the maximum diameter and volume of ablation before TA and at each follow-up point. P < 0.05 was considered statistically significant.

61 patients with Bethesda IV thyroid nodules were evaluated, including 30 patients of ultrasound-guided TA treatment and 31 patients of surgical treatment. The general data are provided in Table 1 . In the TA group, there were four males (13.33%) and 26 females (86.67%) aged between 18-68 years (mean 47.3 ± 13.6 years). The surgery group included eight (25.81%) males and 23 (74.19%) females aged between 23–67 years (mean: 48.9 ± 12.5 years). There were no differences between the two groups, including age and sex (P > 0.05). Ultrasound characteristics of all the nodules are shown in Table 1 . For the TA group, the nodule maximum diameter and nodule volume were 2.46 ± 1.37 cm and 6.56 ± 9.09 ml. For the surgery group, the nodule maximum diameter and nodule volume were 2.47 ± 1.35 cm and 6.42 ± 7.10 ml. There were no significant differences between the two groups (P > 0.05). The ultrasound characteristics of all thyroid nodules including position, composition, echogenicity, shape, margin, and echogenic foci also showed no significant differences between the two groups (P > 0.05).

The 30 patients undergoing TA were performed in accordance with the surgical plan. Immediate contrast-enhanced ultrasound showed that the ablation area was not enhanced, as the maximum diameter and volume was larger than the tumor, which then decreased gradually during the mean 16.4 ± 5.2months follow-up period ( Table 2 , Figure 2 ). There were significant differences in the maximum diameters between baseline and each follow-up point (P <0.001), except for immediately and 3 months after ablation (P > 0.05) ( Table 2 ). The tumor volume showed significant differences between the volume at baseline and that at each follow-up point (P <0.001) ( Table 2 ). The VRR gradually increased with the extension of follow-up time, and significant differences in the VRR were found at each follow-up point before 24 months (P <0.001) ( Table 2 , Figure 3 ). No recurrences, no metastatic lymph node, and no distant metastases were detected during the follow-up.

All patients successfully underwent surgery under general anesthesia, and the histological evaluation of surgical specimens was conducted by experienced pathologists from our department. The pathological results of 31 patients included follicular adenomas (16 cases, 51.61%), Hürthle cell adenomas (2 cases, 6.45%), nodular goiters (2 cases, 6.45%), follicular thyroid carcinoma (FTC) (3 cases, 9.68%) [1 of T1bN0M0 and 2 of T2N0M0, according to The American Joint Committee on Cancer TNM system for differentiated thyroid cancer (17)] including 2 minimally invasive carcinomas, non-invasive follicular thyroid neoplasm with papillary-like nuclear features (1 case, 3.23%), and follicular tumor of uncertain malignant potential (7 cases, 22.58%).

Of the 30 patients in the TA group, only one patient had postoperative pain after ablation, which resolved spontaneously in 2 hours. For the surgery group, 31 patients had postoperative pain. Thyroid function was assessed 1 month after surgery. Four patients were diagnosed with hypothyroidism and received prescriptions for levothyroxine sodium, and one patient had subclinical hypothyroidism. Parathyroid function was assessed 1 day and 1 month after surgery. Four patients had transient hypoparathyroidism, three of which were asymptomatic; the remaining patient had mild facial paresthesia. The serum parathyroid hormone and calcium level of all the four patients were restored within 3 months after calcium supplement treatment. Therefore, a significant difference was noted ( Table 3 ) when compared with the TA group. The TA group had a shorter operation time, smaller incision length, less blood loss, shorter hospitalization time, and lower treatment costs compared to the surgery group (all P <0.001, Table 4 ).