Upgraded hydrodissection and its safety enhancement in microwave ablation of papillary thyroid cancer: a comparative study

Abstract Objectives To study the efficacy and safety of an improved hydrodissection protocol based on the perithyroidal fascial space during microwave ablation for papillary thyroid carcinoma (PTC). Methods The data of 341 patients (94 men and 247 women, median age 41 years old, 25%–75% interquartile range 34–53 years old, nodule maximum diameter 0.2–1.9 cm) who underwent microwave ablation for PTC were retrospectively reviewed. Among them, 185 patients underwent traditional hydrodissection and served as a control group, and 156 patients underwent improved hydrodissection based on perithyroidal fascial spaces, constituting the improved group. Improvements in safety were analyzed by comparing complications between the two groups. The characteristics of hydrodissected spaces, complications, and follow-up results were recorded. Results Hydrodissection was successfully performed in all enrolled patients according to the protocol. The incidence of hoarseness caused by recurrent laryngeal nerve injury, the most common complication in thermal ablation of thyroid nodules, was significantly lower in the improved group than in the control group (1.9% vs. 8.1%, p = 0.021). The median hoarseness recovery time in the improved group was shorter than that in the control group (2 months vs. 3 months, p = 0.032). During follow-up, no local recurrence was encountered in either group. The tumor disappearance rate was not significantly different between the two groups (69.9% vs. 75.7%, p = 0.228). Conclusions Improved hydrodissection based on perithyroidal fascial spaces had better protective effects than traditional hydrodissection.

Several vital structures surround and are tightly adjacent to the thyroid lobe, including the esophagus, trachea, nerves, and blood vessels.Injury to any of the above structures can result in serious complications.Among these structures, the recurrent laryngeal nerve (RLN) is very sensitive to heat injury.However, in most circumstances, it is not detectable on US.RLN injury is the most common complication associated with thermal ablation of thyroid nodules [3].Therefore, safe and effective ablation is challenging, especially when the thyroid nodule is relatively large or adjacent to the RLN or other vital structures [14].
Hydrodissection has traditionally been applied to improve safety during ablation, but it has not been thoroughly described in most studies [15,16].To date, few studies have focused on hydrodissection techniques.According to our experience with thousands of cases of thermal ablation for thyroid nodules, hydrodissection based on perithyroidal fascial spaces is a significant improvement compared with traditional hydrodissection, and it markedly increases ablation safety.
In the present study, an improved hydrodissection protocol based on fascial spaces surrounding the thyroid was first established and investigated by focusing on the fascial space that should be hydrodissected, the manner and degree of hydrodissection, and technical details.The aim of the present study was to evaluate the safety of improved hydrodissection by comparing it with traditional hydrodissection during MWA for PTC.

Materials and methods
This retrospective study was approved by the institutional review board of China-Japan Friendship Hospital.Written informed consent was obtained from each patient before the ablation procedure.The patients consented to publishing their examination results and radiological images anonymously, and written informed consent for publication of their data were waived by the ethics committee of China-Japan Friendship Hospital.

Patients
From June 2015 to December 2020, a total of 1105 patients underwent MWA for thyroid nodules at our center, including 455 PTC patients.The traditional hydrodissection technique, in which isolating fluid was simply injected around the thyroid, was used from June 2015 to September 2019, and patients undergoing this procedure were allocated to the control group.With growing experience, an improved hydrodissection procedure was established based on the perithyroidal fascial space from October 2019 to December 2020 and patients undergoing this procedure were allocated to the improved group.Therefore, in the present study, the clinical data of patients with PTC who underwent MWA with traditional or improved hydrodissection were retrospectively reviewed.The inclusion criteria were as follows:

Preablation assessment
A Logiq E9 (GE Healthcare, US) with a 9.0-MHz linear probe was used to guide the puncture and perform the imaging assessment.The largest diameter and the location of the nodules were measured and recorded.Each measurement was performed by three doctors, and the average was recorded as the final result.

The anatomy of perithyroidal fascial spaces for improved hydrodissection
In the present study, a total of three anatomical perithyroidal fascial spaces were hydrodissected with an improved protocol for separating thyroid lobes far from adjacent vital structures and guaranteeing a safe procedure.These spaces included: (1) the anterior cervical space (ACS), which is located between the infrahyoid muscles (infrahyoid fascia) and thyroid (visceral fascia), and could protect infrahyoid muscles and the carotid sheath from heat injury after hydrodissection; (2) the visceral space (VS), which is between the thyroid and trachea and could protect the trachea, esophagus, RLN, and superior laryngeal nerve (SLN) after hydrodissection; and 3) the post-thyroid space (POTS), which is posterior to the thyroid and carotid sheath and includes the retropharyngeal space and/or danger space (surrounded by the alar fascia, buccopharyngeal fascia, and prevertebral fascia); this space could protect the carotid sheath, RLN and stellate ganglion.The VS at the level of the suspensory ligament of the thyroid gland could not be hydrodissected because of the suspensory ligament.A schematic of the spaces is shown in Figure 2.

Traditional and improved hydrodissection procedures
Before hydrodissection, 1% lidocaine was subcutaneously injected at the proposed puncture point.Then, an 18-G core needle connected to the extension tube and a syringe was inserted, and normal saline (NS) was injected through the neck tissues layer by layer guided by US.For traditional hydrodissection, the needle tip was placed close to the thyroid capsule, corresponding to the target nodule.NS was injected until the important structures were separated at least 5 mm from the thyroid lobe (Figure 3(A,C)), and the needle was then withdrawn.For improved hydrodissection, if the soft tissue or thyroid tissue surrounding the needle tip became swollen during injection of NS, the needle tip was judged to be in the incorrect position and needed precise adjustment guided by US.If the NS widened the space and formed an anechoic area, the needle tip was in the correct fascial space.NS was continuously injected, and the needle tip could be adjusted within the space and fixed at the planned position.The fascial space under successfully improved hydrodissection was characterized by the following features: (1) obvious and smooth borders, one of which was the thyroid capsule; (2) the range and extent of liquid diffusion exactly matched the anatomical fascial spaces; and (3) formation of an anechoic, hypoechoic or mixed-echoic isolating band inside the fascial space after injection and pushing the surrounding critical structures away from the thyroid lobe (Figure 3(B,D)).
The employed hydrodissection strategies depended on the characteristics of the nodules.Generally, hydrodissection of one fascial space is sufficient to protect vital structures if the PTC nodule is small and adjacent to only one space.
However, the hydrodissection of multiple fascial spaces is necessary if the nodule is relatively large or adjacent to more spaces and vital structures.In the present study, the nodule location and corresponding fascial spaces needing hydrodissection were divided into the following types: (1) above the suspensory ligament of the thyroid gland and located near the anterior thyroid capsule and trachea, where ACS and VS isolating fluid was injected (Figure 4

MWA procedure
Ablation was performed by two radiologists with more than 5 years of experience in microwave ablation for thyroid nodules.The whole procedure was performed under local anesthesia.Patients were placed in the supine position with the neck extended.After the neck was sterilized, and hydrodissection was performed according to the above protocols, a 0.5% lidocaine mixture was injected along the thyroid capsule to relieve pain during ablation.MWA was performed guided by US with a cooled MWA antenna (17 gauge) with a 0.35-cm active tip (Intelligent Basic Type Microwave Tumor Ablation System, Nanjing ECO Microwave System, Nanjing, China or KY-2000 microwave system, Kangyou Medical, Nanjing, China).The power was 30 W. A multiple point ablation strategy was employed [17].During ablation, the isolating fluid was continuously injected to prevent heat injury in the improved group.Complete ablation was defined as the nonenhancement ablation zone completely covering the PTC tumor and extending at least 2 mm from the original PTC margin on contrast-enhanced US.The complications of the patients were observed and recorded.

Postablation assessment and follow-up visit
Technical success was defined as the complete absence of enhancement on CEUS at the end of every procedure.After ablation, all patients underwent follow-up every 3 months during the first year and every 6 months thereafter.The end of follow-up was set at two years.A residual tumor was defined as the ablation zone failing to cover the original tumor completely after ablation on US examination.Local recurrence refers to tumor growth along the ablation zone during follow-up on US examination.Tumor disappearance refers to complete absorption of the ablation zone on US.The follow-up included thyroid US and thyroid function tests.If the patient had hoarseness, the movement of the vocal cord was evaluated with US, as well as laryngoscopy, at each follow-up.

Statistical methods
Statistical analyses were performed using SPSS software, version 24.0 (IBM, Armonk, NY, USA).Data are presented as the mean ± standard deviation (SD) for normal distributions, and the median and 25%-75% interquartile range (IQR) were used if data did not fit a normal distribution.The independent two-sided Mann-Whitney U test was used to test the differences between the medians of continuous variables for data that did not fit a normal distribution.All differences were considered significant when p < 0.05.

Demographic and tumor characteristics
A total of 341 patients were enrolled in the present study, which included 94 men and 247 women.The median age of the patients was 41 (25%-75%; IQR 34-53; age range 20-80) years old.Among them, 185 patients were in the traditional group, and 156 were in the improved group.The baseline characteristics, including age, sex ratio, tumor location, and maximum diameter of the PTC nodule, were not significantly different between groups (p > 0.05).The characteristics of the patients and nodules are summarized in Table 1.

Hydrodissection procedure results
Traditional hydrodissection and improved hydrodissection were successfully performed in all enrolled cases according to the protocol.The details of the improved hydrodissection are summarized in Table 2.Among them, ACS isolating fluid was injected in 66 of 156 (42.3%) cases, VS in 110 of 156 (70.5%) cases (including 10 cases at the suspensory ligament of the thyroid gland), and POTS in 126 of 156 (80.8%) cases.All three spaces were hydrodissected in 7 cases, two spaces in 132 cases, and one space in 17 cases.The ACS isolating fluid formed a hypoechoic isolating band and pushed the infrahyoid muscles and carotid sheath away from the thyroid in all cases.The VS isolating fluid could form a stable isolating band and push away the trachea and esophagus.However, at the suspensory ligament of the thyroid gland, the isolating fluid could not form a stable isolating band but   instead formed hypoechoic swelling area in the ligament, and an $0.2-0.3 cm distance from the trachea and TEG to the corresponding thyroid lobe was maintained by mild-pressure continuous injection during ablation.The POTS isolating fluid could form a stable hypoechoic isolating band and push away the surrounding muscles and carotid sheath.

Adverse effects during hydrodissection
The patients only reported various degrees of tension pain during isolating fluid injection.Hypertension with systolic blood pressure >180 mm Hg or diastolic blood pressure greater than 120 mm Hg was encountered in five (5/341, 1.5%) cases, including two cases in the improved group and three cases in the control group.Twelve patients (12/341, 3.5%) had hemorrhages, including six cases in the control group and six cases in the improved group.The US characteristic of hemorrhage is the echo changing from anechoic isolating fluid to hyperechoic blood clot.The hemorrhages stopped spontaneously in 10 cases.Ablation hemostasis was performed in the other two cases.The incidences of hypertension and hemorrhage were not significantly different between the two groups (p > 0.05).

Ablation outcome
The complete absence of enhancement on CEUS was observed in all target tumors after ablation.The technical success rate was 100% in both groups.The incidence of hoarseness in the improved group was markedly lower than that in the control group (3/156, 1.9% vs. 15/185, 8.1%, p ¼ 0.021).The median hoarseness recovery time in the improved group was shorter than that in the control group (2 months vs. 3 months, p ¼ 0.032).
During the two-year follow-up period, no residual tumors were encountered in either group.The available population of the two groups at the 1st month was 156-185; at the 3rd month, it was 144-160; at the 6th month, it was 150-166; at the 9th month, it was 126-118; at the 12th month, it was 151-172; at the 18th month, it was 135-144; and at the 24th month, it was 148-171.The tumor disappearance rate in the traditional hydrodissection group was 75.7% (140/185), and that in the improved hydrodissection group was 69.9% (109/156) at the end of follow-up.The tumor disappearance rate was not significantly different between the two groups (p ¼ 0.228).

Discussion
The incidence of PTC has been increasing rapidly over the past 10 years.Compared with other malignant tumors, PTC is an indolent carcinoma with a relatively good prognosis.The traditional treatment for PTC is thyroidectomy.With the development of minimally invasive techniques, thermal ablation of PTC has rapidly developed due to its undisputed advantages, such as minimal invasiveness, safety, effectiveness, and thyroid function preservation.Ensuring safety is one of the key factors for the thermal ablation of PTCs.The thyroid gland is in close proximity to important structures, such as the trachea, esophagus, nerves, and great blood vessels, and damage to any of the above structures can induce serious complications.High-frequency US can display most of these structures [18].However, thin nerves, especially SLNs and RLNs, are not only invisible on US in most situations but are also vulnerable to heat injury.The incidence of RLN injury with MWA, radiofrequency ablation and laser ablation for PTC in prior studies was 3.3%-5.2%[14,19], 1.4%-2.9%[20,21], and 0.5% [22], respectively.Generally, hydrodissection is the key technique to ensure safety during ablation, but it has not been described in detail in previous studies.To date, hydrodissection remains an empirical procedure, and specific studies on the details of the hydrodissection technique are lacking.
Unified standards are not available for an empirical procedure.Therefore, the incidence of complications associated with thermal ablation for PTC varies significantly in the literature, and most of the cases enrolled have been only small PTCs far from the thyroid capsule [23].For larger nodules and nodules located near dangerous areas, the RLN injury rate could be higher [3].In the present study, a standard hydrodissection technique was established based on the perithyroidal fascial space by summarizing the clinical experience of hundreds of PTC cases undergoing thermal ablation and combining this clinical experience with the anatomical theory of the perithyroidal fascial space.In fact, the standardized hydrodissection procedure is similar to blunt separation during thyroidectomy; both could guarantee a safe procedure.For improved hydrodissection, several key factors have been described, mainly including the details of improved hydrodissection, the fascial space that should be hydrodissected, how many fascial spaces should be hydrodissected, the degree of hydrodissection, how to perform the hydrodissection and how to evaluate the hydrodissection effect.
Generally, several fascial spaces surround the thyroid, mainly including the anterior cervical fascia space, pretracheal (visceral) fascia space, and retropharyngeal space [ 24,25].The results of the present study showed that all enrolled patients underwent successful improved hydrodissection based on the above fascial spaces, and no serious complications occurred during the procedures.During hydrodissection, an 18-gauge core needle was used because it could be clearly displayed on US and was beneficial to precise puncturing guided by US.During puncture, color Doppler flow imaging (CDFI) was used to disclose blood vessels on the pathway and remind the operator to avoid injury to them.The air in the core needle, extension tube and syringe was exhausted before isolating fluid injection to avoid influencing the quality of the US images.A few patients experienced hypertension during hydrodissection.Identifying the specific reason for hypertension, whether nervousness, pain, or increased tension from isolating fluid, is difficult.However, all cases of hypertension recovered after ablation.Injury to vessels during hydrodissection could lead to hemorrhage, and large hematomas could influence the effectiveness of hydrodissection and US image quality.CDFI before puncture was important to display the vessel in the puncture pathway and avoid injury to vessels.The characteristic of bleeding is an echo change from anechoic liquid to a hyperechoic blood clot, which could remind the operator to manage it.
Compared with the traditional group, the improved group had a significantly lower incidence of RLN injury, and the recovery time after injury was shorter, demonstrating that the degree of injury in the improved group was mild.In addition, the rate of RLN injury in the improved hydrodissection group was even lower than the rate reported in the literature for thyroidectomy (3.9%-7.9%)[26][27][28].Furthermore, the therapeutic effect, including the incidence of residual tumor and the tumor disappearance rate, was not significantly different between the two groups.
In summary, improved hydrodissection based on perithyroidal fascial spaces has several advantages.This improved procedure uses isolating fluid to fill the fascial space and separate the thyroid gland far from the surrounding important structures without damaging the fascial structure, and it could prevent postoperative adhesions.By maintaining the isolating band thickness through continuously injection of isolating fluid, heat transmission could be limited inside the thyroid capsule.This technique is conducive to the protection of nerves and other important structures running in the fascial space, and it reduces the complications of thermal ablation.The above advantages explain the lower rate of complications and milder injury to nerves in the improved group.The above results demonstrate that improved hydrodissection based on the perithyroidal fascial space could guarantee a safer procedure in MWA of small PTCs.Moreover, it also ensures a safe procedure for larger PTCs or those located in dangerous locations.
The present study was subject to several limitations.First, there is often selection bias in a retrospective study.Second, the patients did not undergo postoperative laryngoscopy if no significant voice change was encountered after ablation, and the real rate of RLN might be underestimated in cases of asymptomatic nerve injuries.Third, the fascial spaces on US were based on radiological speculation for corresponding anatomical structures, and gross specimens were lacking.Fourth, the complication rate was low, which could have led to statistical bias.

Conclusions
The application of improved hydrodissection based on perithyroidal fascial spaces could ensure the safety and effectiveness of ablation procedures and had a better protective effect than traditional hydrodissection.

( 1 )
PTC confirmed by US-guided fine-needle aspiration biopsy; (2) patients who refused or were ineligible for surgery; and (3) follow-up time of at least 12 months.The exclusion criteria were: (1) PTC with capsular invasion or local/distant metastasis; (2) incomplete follow-up data; (3) patients who had undergone partial thyroidectomy before ablation; and (4) patients with multifocal PTC nodules.The flow chart of patient selection is shown in Figure 1.
(A)); (2) at the suspensory ligament of the thyroid gland and located near the tracheoesophageal groove (TEG), where mild-pressure continuous isolating fluid injection in the VS and POTS is necessary for hydrodissection and swelling of the suspensory ligament of the thyroid gland (Figure 4(B)); (3) near the anterior thyroid capsule, where ACS isolating fluid was injected (Figure 4(C)); (4) at the isthmus, where ACS and mild-pressure continuous VS isolating fluid were injected (Figure 4(D)); (5) only near the lateral thyroid capsule, where ACS and POTS isolating fluid were injected (Figure 4(E)); (6) below the suspensory ligament of the thyroid gland and near the TEG, where the VS and POTS were injected (Figure 4(F)); and (7) at the inferior part of the thyroid, near the TEG and anterior thyroid capsule, where ACS and the VS isolating fluids were injected (Figure 4(G)).

Figure 2 .
Figure 2. Schematic drawing of the main structures around the thyroid at different cervical levels and hydrodissected fascial spaces.(A) Hydrodissected spaces at the C4-5 level.The infrahyoid muscles could be protected by hydrodissecting the ACS (1).The SLN (green circle and arrowhead) could be protected by the hydrodissected VS (2).The carotid sheath and surrounding muscles could be protected by the POTS (3), isolating fluid.(B) Hydrodissected spaces at the C6 level.The RLN (yellow circle and black arrowhead) could be protected by hydrodissected VS.Hydrodissection was restricted by the suspensory ligament of the thyroid gland (red arrowhead).The trachea could be protected by the hydrodissected VS. (C) The hydrodissected spaces at the C7 level.RLN (yellow circle, black arrowhead) could be protected by hydrodissected VS. (D) Hydrodissected spaces below the C7 level.The RLN (yellow circle and black arrowhead) could be protected by the hydrodissected VS.

Figure 3 .
Figure 3. US images of traditional hydrodissection and improved hydrodissection.(A) Traditional hydrodissection before ablation.The strap muscles were swollen (white arrow), and a mixed echoic isolating band formed in this situation; the thyroid and anterior muscle were not effectively separated.(B) Improved hydrodissection in the ACS.The isolating fluid formed an anechoic isolating band (white arrow) and separated the strap muscles, effectively limiting the heat within the thyroid capsule.(C) Traditional hydrodissection before ablation.The hydrodissection area was filled with swollen soft tissue (white arrow).(D) Improved hydrodissection at the VS and POTS.The isolating fluid formed an anechoic isolating band (white arrow) and separated the muscles and trachea.

Figure 4 .
Figure 4. (A-G) US images of improved hydrodissection, as well as a schematic diagram of target nodules (white arrow) at different locations.The ACS hydrodissection (black arrow), VS hydrodissection (white arrowhead), and post-thyroid hydrodissection (black arrowhead) are shown as hypoechoic or mixed echoic bands on the images.The flow directions of the isolating fluid are shown as white thin arrows.

Table 1 .
Baseline characteristics of the enrolled patients.

Table 2 .
Hydrodissection strategies according to the location of the thyroid nodule.