Factors associated with initial incomplete ablation for benign thyroid nodules after radiofrequency ablation: First results of CEUS evaluation

Abstract

OBJECTIVE: To assess the factors associated with initial incomplete ablation (ICA) after radiofrequency ablation for benign thyroid nodules (BTNs).

MATERIALS AND METHODS: 69 BTNs (mean volume 6.35±5.66 ml, range 1.00–25.04 ml) confirmed by fine-needle aspiration cytology (FNAC) in fifty-four patients were treated with ultrasound-guided percutaneous radiofrequency ablation (RFA) and the local treatment efficacy was immediately assessed by intra-procedural contrast-enhanced ultrasound (CEUS). The RFA was performed with a bipolar electrode (CelonProSurge 150–T20, output power: 20 W). CEUS was performed with a second generation contrast agent under low acoustic power (i.e. coded phase inversion, CPI). Characteristics of clinical factors, findings on conventional gray-scale ultrasound, color-Doppler ultrasound, and CEUS were evaluated preoperatively. Factors associated with initial ICA and initial ICA patterns on CEUS were assessed. Volume reduction ratios (VRRs) of ICA nodules were compared with those with complete ablation (CA).

RESULTS: The RFA procedures were accomplished with a mean ablation time and mean total energy deposition of 11.13±3.39 min (range, 5.38–22.13 min) and 12612±4466 J (range, 6310–26130 J) respectively. CEUS detected initial ICA in 21 of 69 (30.8%) BTNs and 16 (76.2%) of the 21 BTNs with initial ICA achieved CA after additional RFA, leading to a final CA rate of 92.8% (64/69). The factors associated with initial ICA were predominantly solid nodule, nodule close to danger triangle area, nodule close to carotid artery, and peripheral blood flow on color-Doppler ultrasound (all P < 0.05). The mean VRRs of all BTNs were 23.4%, 54.4% and 81.9% at the 1-, 3- and 6-month follow-up, respectively. All BTNs achieved therapeutic success in this series in that all had VRRs of >50% at the 6-month follow-up, among which 7 nodules (10.1%) had VRRs of >90%. There were significant differences in VRRs between ICA nodules and CA nodules at the 3- and 6-month follow-up (all P < 0.05).

CONCLUSION: The factors associated with initial ICA after RFA for BTNs were predominantly solid nodules, nodule close to danger triangle area, nodule close to carotid artery, and peripheral blood flow on color-Doppler ultrasound. CEUS assists quick treatment response evaluation and facilitates subsequent additional RFA and final CA of the nodules. Nodules with CA achieve a better outcome in terms of VRR in comparison with those with ICA.

Keywords

Radiofrequency ablation contrast-enhanced ultrasound incomplete ablation ultrasound thyroid

Abbreviation

RFA

Radiofrequency ablation

CEUS

Contrast-enhanced ultrasound

3D-CEUS

Three-dimensional contrast-enhanced ultrasound

CSI

Contrast specific imaging

CPI

Coded phase inversion

PIHI

Pulse inversion harmonic imaging

FNAC

Fine-needle aspiration cytology

Ultrasound

Complete ablation

ICA

Initial incomplete ablation

ROI

Region of interest

VRR

Volume reduction ratio

PEI

Percutaneous ethanol injection

BTN

Benign Thyroid Nodule

Thyroid nodule

IRE

Irreversible electroporation

TIC

Time intensity curves

1 Introduction

Thyroid nodule (TN) is a common problem in adults and its prevalence increases with age [10]. Most TNs are benign, but some patients require treatment for subjective symptoms, cosmetic reasons, or anxiety about a possible malignant change [9]. The conventional treatment method for benign thyroid nodules (BTNs) is surgery. However, complications associated with surgery such as hypoparathyroidism, laryngeal nerve injury or bleeding cannot be neglected [2, 11]. On the other hand, ultrasound (US) -guided ablation for BTNs as a minimally invasive procedure has gained increasing attention in recent years and has been endorsed by some guidelines such as American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi and European Thyroid Association (AACE/AME/ETA) guidelines and Korean Society of Thyroid Radiology guideline [7, 19]. The major goal of US-guided ablation procedure such as radiofrequency ablation (RFA) is to reduce the volume of the BTNs and thus alleviate the related symptoms and anxiety. According to the literatures, volume reduction ratio (VRR) of BTNs after RFA ranges from 75% –97% [3, 14], which confirms RFA is an effective and promising treatment method for BTNs. The other advantages of RFA include low complication rate, short hospital stay, and no cosmetic concern [7 , 19].

As a thermal ablation method, RFA induces heat deposition in BTNs and causes in situ coagulation necrosis of BTNs. In this process, the intranodular blood vessels are destructed and the BTNs will shrink in the follow-up [23]; however, if the intranodular blood vessels are not destructed, viable tissue may remain in the BTNs, which may result in nodule regrowth during the follow-up period and may not result in significant volume reduction [3]. Therefore, the strategy of RFA is to destruct the blood vessels in nodule tissue as much as possible and to gain complete ablation (CA) of the BTN in a safe way. As a consequence, accurate evaluation of the status of the intranodular blood vessels is crucial for treatment planning and follow-up strategy. Conventional gray-scale US and color-Doppler US are widely used in this field; however, they are not reliable and sensitive in assessing tiny intranodular blood vessels [5, 15].

In recent years, contrast-enhanced ultrasound (CEUS) has gained attention for diagnosis of thyroid nodules since it provides both microcirculation and macrocirculation information of the nodules[20 , 29]. On CEUS, ring enhancement during the arterial phase is predictive of benign TNs, whereas heterogeneous enhancement is suspicious of malignant TNs [29]. CEUS quantitative method such as time intensity curve (TIC) analysis is also useful for the differentiation between benign and malignant TNs [24]. In addition, CEUS can evaluate the post-treatment efficacy of RFA for BTNs[16, 28], as it does in evaluating the post-treatment efficacy for liver tumors [4, 25]. Usage of US contrast medium is also recommended for treatment response evaluation after ablation procedure according to the AACE/ACE/AME Guideline [7].

In clinical practice, it is relevant to identify the un-ablated residual tissues in the BTNs in the same treatment session; otherwise, re-ablation has to be performed, which increases the medical cost and patient would discomfort. Therefore, to understand the associated factors for initial incomplete ablation (ICA) of BTNs after RFA may help the operators to overcome them and special maneuvers can be carried out in the same session when encountering these factors, which might reduce the cases with ICA and avoid the shortcomings such as prolonging the procedure time, increasing the cost and complication rate. Unfortunately, no study has been performed yet to assess the factors associated with initial ICA in RFA for BTNs. Therefore, the present study was carried out with an aim to assess the factors associated with initial ICA in a series of consecutive patients during RFA.

2 Materials and methods

This retrospective study was approved by the institutional review board of the university hospital. The requirement to obtain informed consent was waived because of the retrospective nature of the study, but a written informed consent was obtained from each subject before RFA after full explanation of the purpose and nature of the procedure used.

2.1 Patients

From November 2013 to October 2015, 72 consecutive patients with BTNs were subjected to US-guided RFA in the university hospital. The inclusion criteria for all the patients were as follows: (a) Presence of subjective symptoms (compressive symptom, neck discomfort, foreign body sensation) or cosmetic problems; anxiety about a malignancy; unsuited for surgery or unwilling to undergo surgery. (b) Confirmation of benign natures (Bethesda Class II) at fine-needle aspiration cytology (FNAC). (c) Without malignant features at US (i.e., taller than wide, spiculated margin, marked hypoechoic, microcalcifications, etc.). (d) Complete blood counts, blood coagulation tests, and serum levels of thyroid hormone, thyrotropin, and calcitonin within normal limits. Among them, 18 patients were excluded from the study for the following reasons: 3 patients had intractable pain during the procedure and the treatment was stopped with some untreated portions left in the nodules; 9 patients require additional treatment sessions because of large nodule size; 6 patients whose data were incomplete. Finally, 69 benign nodules (mean volume 6.35±5.66 ml, range 1.00–25.04 ml) in 54 patients (39 patients had one nodule, 15 patients had two nodules) were included for the analysis. US-guided FNAC was performed using a 22-gauge PTC needle under local anesthesia. Three to five smears were obtained for each target nodule, which were reported according to the Bethesda System for Reporting Thyroid Cytopathology [6].

2.2 Pre-treatment US assessment

Before ablation, all the patients underwent conventional US examination including gray-scale US, color-Doppler US, and CEUS examination. The conventional US and CEUS examinations wereperformed by one of two radiologists with more than 10 years’ experience in thyroid imaging. A Logiq E9 US machine (GE Medical Systems, Milwaukee, WI, USA) equipped with a ML6-15 liner transducer with a center frequency of 12 MHz (range: 4–15 MHz) was used for gray-scale US examination and color-Doppler US. Conventional transverse and longitudinal US images were obtained for each target nodule. The volume of the nodule was calculated using the following equation based on diameter measurement with US: V = π a · b · c/6 (V: volume, a: the largest diameter, b and c: the other two perpendicular diameters). Another 9-4 linear transducer with a center frequency of 7 MHz (range: 2–8 MHz) was used for CEUS evaluation. The installed contrast specific imaging (CSI) mode was coded phase inversion (CPI) at a low mechanical index (<0.2). CPI is based on pulse inversion harmonic imaging (PIHI) and can enable effective tissue cancellation and avoid destruction of microbubbles in the circulation. SonoVue (Bracco, Milan, Italy), as a second generation US contrast agent, consists of phospholipid-stabilized shell microbubbles filled with sulfur hexafluoride gas. The contrast agent was injected as an intravenous bolus of 2.4 mL via a 20 gauge cannula into antecubital vein and followed by a 5 ml of 0.9% sterile saline solution flush. Dynamic CEUS examination was then performed separated for each TN. The thyroid nodule was observed continuously for 2 minutes. All the images of US, color-Doppler US, and CEUS were digitally recorded for further analysis.

2.3 Ablation procedure

All procedures of RFA were performed by one radiologist with 6 years’ of experience in RFA for BTNs. For RFA, a bipolar RFA (BRFA) instrument (Celon AG Medical Instruments, Teltow, Germany), consisting of an RF generator with a frequency of 470 KHz and maximum power output of 250 W was applied. The RFA system is designed as a bipolar unit and no grounding pads are needed, which technically overcomes the disadvantages of using grounding pads. One of two types BRFA electrodes was used (CelonProSurge 150-T09, 18 gauge, 15 cm long with a conducting part of 9 mm in length, output power: 3 W; and CelonProSurge 150-T20, 15.5 gauge, 15 cm long with a conducting part of 20 mm in length, output power: 20 W). For 150-T20, an internally cooled electrode was provided with a triple peristaltic pump perfusing 0.9% NaCl solution at a rate of 30 mL/min. The BRFA system continuously estimates the tissue resistance and power output automatically stops if resistance exceeds a specific limit (i.e.700 Ω).

Local anaesthesia with 2% lidocaine was applied to the puncture site. And a 2 mm incision in length was performed with a scalpel. Under US guidance, hydrodissection technique was applied that 2% lidocaine and 0.9% normal saline were mixed and injected into the surrounding thyroid capsule, which can provide a safe thermal barrier to ablation energy and avoid damage to adjacent critical structures [28]. The trans-isthmic approach was generally performed and an elaborative observation was necessary to avoid damage to the nerves and vessels along the approach route [21]. The BRFA was performed in the transverse US view by the moving-shot technique [21]. Ablation was terminated when all conceptual ablation units of the nodule had changed to transient hyperechoic zones.

2.4 Initial local treatment efficacy assessment

Initial local treatment efficacy was evaluated by CEUS for 5–10 min after RFA until the hyperechoic cloud during the RFA procedure disappeared. CEUS was used as gold standard according to a recently released AACE/ACE/AME Guideline in which CEUS is recommended for the assessment of the area of necrotic zones after US-guided ablation procedures [7]. Conventional US was not used as the gold standard since during the ablation procedure the ablated area would be covered by vapors generated from RFA, which appears as hyperechoic on conventional US and obscures the treated area [15]. On the other hand, color-Doppler US is not sensitive in detecting small vessels and slow blood flow [5].

When the nodule showed complete non-enhancement within the nodule during both arterial phase and venous phases, complete ablation (CA) was defined; while ICA was defined as persistence of enhancement within the nodule after treatment, as a sign of residual viable tissue. For the cases with initial ICA, additional ablation was carried out to ablate the enhancement areas on CEUS with an aim to destroy the viable tissue as much as possible, while at the same time the treatment safety was firstly considered. CEUS was carried out again to evaluate the treatment response after additionalRFA.

2.5 Post-procedural follow-up

Post-procedural follow-up was carried out at 1, 3, 6 months after treatment. In each follow-up, US examination, CEUS and thyroid serum test were performed. Volume reduction ratio (VRR) of the treated nodule was calculated. VRR was calculated using the following equation according to the volume measurement on conventional US: VRR = [(initial volume - final volume) ×100% ] / initial volume. A VRR greater than 50% at 6 months follow-up was considered as therapeutic success, otherwise therapeutic failure was defined [22]. Any adverse event which occurred during the follow-up period was also recorded.

2.6 Evaluation of possible associated factors for initial ICA

To evaluate the possible associated factors for initial ICA after RFA, all images of conventional gray-scale US, color-Doppler US and CEUS were evaluated independently by two experienced investigators with more than 5 years’ experience in thyroid US, who were blind to the patients’ identities. When discordance appeared for the evaluation between the two investigators, another senior investigator with more than 10 years of experience in thyroid US reviewed the images and made the final decision.

The composition of the nodules was classified as predominantly solid (solid portion ≥50%) or predominantly cystic (solid portion <50%). The location of the target nodules was divided into three positions: in contact with trachea or away from trachea, contact with carotid artery or away from carotid artery, and contact with danger triangle area or away from danger triangle area (i.e. the area of the thyroid nodule adjacent to the recurrent laryngeal nerve and/or the esophagus). Nodule vascularity on color-Doppler US were defined as no signal in the nodule (type 0), signals in <25% of the nodule (type 1), signals in 25% –50% of the nodule (type 2), and signals in >50% of the nodule (type 3). Distribution of nodule vascularity on color-Doppler US were divided as periphery vascularity or absent of periphery vascularity. On CEUS, the enhanced extent of the solid portion of nodule was referred to adjacent thyroid parenchyma and was divided into hypo-, iso- and hyper-enhancement in arterial phase (i.e. 15–45 s after contrast administration). According to the shape of enhancement portion on CEUS, initial ICA patterns were divided into rim-like residual tissue (Fig. 1) and nodule-like residual tissue (Fig. 2).

Fig.1

A 27-year-old female with predominantly solid nodule in the right lobe of thyroid gland. Nodule is close to carotid artery (arrow-head). (A) (B) Axial ultrasound examination reveals baseline volume of the nodule is 3.02 ml. (C) Transverse color Doppler ultrasound shows obvious peripheral rim-like flow in the nodule. Nodule vascularity is defined as type 2. (D) Contrast-enhanced ultrasound before RFA: the nodule shows iso-enhancement during the arterial phase. (E) During RFA, the RFA electrode could be clearly visualized with real-time ultrasound as a hyperechoic line. Ultrasound imaging shows hyperechoic region (arrows) surrounding electrode. (F) Contrast-enhanced ultrasound after initial RFA: the nodule shows rim-like residual enhancement (the area between white line and red line) during the arterial phase. (G) Contrast-enhanced ultrasound after additional RFA: the nodule shows non-enhancement during the arterial phase.

Fig.2

A 51-year-old male with a predominantly solid nodule in the right lobe of thyroid gland. Nodule is close to carotid artery (arrow-head) and danger triangle area (right triangle). (A) (B) Axial ultrasound examination reveals baseline volume of the nodule is 3.53 ml. (C) Transverse color Doppler ultrasound shows peripheral flow in the nodule. Nodule vascularity is defined as type 1. (D) Contrast-enhanced ultrasound before RFA: the nodule shows hyper-enhancement during the arterial phase. (E) During RFA, the RFA electrode could be clearly visualized with real-time ultrasound as a hyperechoic line. Ultrasound imaging shows hyperechoic region (arrows) surrounding electrode. (F) Contrast-enhanced ultrasound after initial RFA: the nodule shows nodule-like residual tissue (the area between white line and red line) during the arterial phase. Nodular-like residual tissue is found close to carotid artery and danger triangle area. (G) Contrast-enhanced ultrasound after additional RFA: the nodule shows non-enhancement during the arterial phase (arrow-heads).

2.7 Statistical analysis

All the statistical analyses were performed using the SPSS software (version 19.0, Chicago, IL, USA). Observer consistency was evaluated through a κ value: slight agreement (κ= 0.00–0.20), fair agreement (κ= 0.21–0.40), moderate agreement (κ= 0.41–0.60), substantial agreement (κ= 0.61–0.80) and almost perfect agreement (κ= 0.80–1.00). Results were expressed as mean±SD (range) if normal distribution was achieved. Continuous variables were compared by independent two-sample t test, while Chi-square test or Fisher’s exact test was used to analyze the categorical variables. Nodule volume and VRRs of “ICA nodules” and “CA nodules” were compared using the Mann–Whitney U tests. P values <0.05 were considered statistically significant. Confidence intervals (CIs) were recorded as two-sided exact binomial 95% CIs.

3 Results

In the study, all patients tolerated well and no major complications were encountered. 2 patients reported mild pain and 1 patient had hematoma in the supcapsular location. A short break of energy output was carried out and the RFA procedure was continued after a while. These minor complications were relieved spontaneously within 1 day after ablation. The mean ablation time and mean total energy deposition were 11.13±3.39 min (range, 5.38–22.13 min) and 12612±4466 J (range,6310–26130 J).

21/69 (30.8%) nodules with initial ICA were detected by intra-procedural CEUS and these ICA nodules underwent additional RFA treatment during the same session. 16/21(76.2%) nodules with initial ICA achieved CA underwent additional RFA treatment, while 5/21(23.8%) nodules with initial ICA were failed to achieve CA due to the following reasons: 4 nodules were close to danger triangle area and 1 nodule was close to carotid artery. Finally, 64/69 (92.7%) nodules achieved CA, while 5/69 (7.3%) nodules were ICA nodules.

The factors associated with initial ICA are shown in Table 1. Those associated factors were predominantly solid nodule (P = 0.007), nodule location close to danger triangle area (P = 0.01), nodule location close to carotid artery (P = 0.043), and periphery blood flow on color-Doppler US (P = 0.023). Conversely, gender, age, nodule position, nodule volume, nodule close to trachea, vascularity on color-Doppler US and enhancement extent on CEUS did not achieve significant differences (all P > 0.05). For the two different reviewers (Reader 1 vs. Reader 2), a perfect agreement was achieved for evaluation of internal nodule component, a substantial agreement was obtained for evaluation of nodule location (i.e. nodule close to trachea, carotid artery and danger triangle area), peripheral flow and CEUS, and a moderate agreement was achieved for evaluation of vascularity on color Doppler US (Table 2). In 8.7% –26.1% of evaluations, the third reader was involved.

Table 1
Factors associated with initial ICA of benign thyroid nodules after RFA

Variable All CA Initial ICA P value

(n = 69) (n = 48) (n = 21)

Gender

Male/Female 20/49 16/32 4/17 0.229

Age (y) 45±15 46±15 44±15 0.722

Range 21–69 21–69 23–67

Nodule position

Left/isthmus/right 28/5/36 23/3/22 8/1/12 0.129

Nodule volume 6.35±5.66 5.92±5.85 7.35±5.21 0.338

Range 1.00–25.04 1.00–25.04 1.33–18.67

Internal nodule component

predominantly solid / predominantly cyst 41/28 23/25 18/3 0.007^*

Nodule location, close to

Trachea

No / yes 28/41 21/27 7/14 0.417

Carotid artery

No / yes 29/40 24/24 5/16 0.043^*

Danger triangle area

No / yes 45/24 36/12 9/12 0.01^*

Vascularity

0/1/2/3 9/43/10/7 7/33/5/3 2/10/5/4 0.143

Peripheral flow

No/yes 34/35 28/20 6/15 0.023^*

CEUS

Hypo-, iso- and hyper-enhancement 26/28/15 21/20/7 5/8/8 0.071

during arterial phase

Variable	All	CA	Initial ICA	P value
Gender
Male/Female	20/49	16/32	4/17	0.229
Age (y)	45±15	46±15	44±15	0.722
Range	21–69	21–69	23–67
Nodule position
Left/isthmus/right	28/5/36	23/3/22	8/1/12	0.129
Nodule volume	6.35±5.66	5.92±5.85	7.35±5.21	0.338
Range	1.00–25.04	1.00–25.04	1.33–18.67
Internal nodule component
predominantly solid / predominantly cyst	41/28	23/25	18/3	0.007^*
Nodule location, close to
Trachea
No / yes	28/41	21/27	7/14	0.417
Carotid artery
No / yes	29/40	24/24	5/16	0.043^*
Danger triangle area
No / yes	45/24	36/12	9/12	0.01^*
Vascularity
0/1/2/3	9/43/10/7	7/33/5/3	2/10/5/4	0.143
Peripheral flow
No/yes	34/35	28/20	6/15	0.023^*
CEUS
Hypo-, iso- and hyper-enhancement	26/28/15	21/20/7	5/8/8	0.071
during arterial phase

^*Indicate the differences are statistically significant. CEUS, Contrast-enhanced ultrasound; CA, Complete ablation; Initial ICA, Initial incomplete ablation; RFA, Radiofrequency ablation.

Table 2

Inter-observer agreement on the interpretation of conventional US and CEUS features

Variable	Reader1	Reader2	κ value
Internal nodule component
predominantly solid / predominantly cyst	38/31	36/33	0.825
Nodule location, close to
Trachea
No / yes	25/44	33/36	0.765
Carotid artery
No / yes	27/42	32/37	0.735
Danger triangle area
No / yes	45/24	44/25	0.779
Vascularity
0/1/2/3	8/39/14/8	9/38/17/5	0.576
Peripheral flow
No/yes	35/33	37/32	0.796
CEUS
Hypo-, iso- and hyper-enhancement	23/31/15	26/26/17	0.666
during arterial phase

With respect to the ICA patterns on CEUS, the factor associated with rim-like residual tissue of ICA was peripheral flow on color-Doppler US (P = 0.046). Conversely, internal nodule component, and nodule close to carotid artery and danger triangle area did not achieve significant differences (all P > 0.05). The factor associated with nodule-like residual of ICA was BTN close to danger triangle area (P = 0.032). Conversely, internal nodule component, nodule close to carotid artery and peripheral flow on color-Doppler US did not achieve significant differences (all P > 0.05) (Table 3).

Table 3

Factors associated with ICA patterns on CEUS

ICA pattern on CEUS (n = 21)	Rim-like residual tissue	Nodule-like residual tissue	P value
	after RFA (n = 8)	after RFA (n = 13)
Internal nodule component
predominantly solid / predominantly cyst	6/2	12/1	0.531
Nodule location, close to
Carotid artery
No / yes	3/5	2/11	0.325
Danger triangle area
No / Yes	6/2	3/10	0.032^*
Peripheral flow
No/yes	0/8	6/7	0.046^*

^*Indicate the differences are statistically significant. ICA, Incomplete ablation; CEUS, Contrast-enhanced ultrasound; RFA, Radiofrequency ablation.

The mean VRRs of all nodules were 23.4%, 54.4%, 81.9% at the 1-, 3- and 6-month follow-up, respectively. All BTNs achieved therapeutic success in this series that all had VRRs of >50% at the 6-month follow-up, among which 7 nodules (10.1%) had VRRs of >90%. The mean VRRs of the final 5 ICA nodules were 19.0%, 47.1% and 74.0% at the 1-, 3- and 6-month follow-up, respectively. And the mean VRRs of the final 64 CA nodules were 24.0%, 55.6% and 82.5% at the 1-, 3- and 6-month follow-up, respectively. There were significant differences in VRRs between ICA nodules and CA nodules at the 3- and 6-month follow-up (all P < 0.05) (Table 4).

Table 4

The change in nodule volume after RFA

	ALL	CA	ICA	P value
	(n = 69)	(n = 64)	(n = 5)
Nodule volume	6.35±5.66 (1.00–25.04)	6.07±5.02 (1.00–25.04)	10.09±6.78 (5.20–21.93)	0.108
1 month VRR (%)	23.4±5.8 (11.3–36.8)	24.0±5.9 (11.3–36.9)	19.0±3.0 (15.7–22.8)	0.065
3 month VRR (%)	54.4±7.0 (33.3–68.6)	55.6±6.6 (34.3–68.6)	47.1±7.9 (33.3–52.7)	0.008^*
6 month VRR (%)	81.9±6.8 (63.3–94.8)	82.5±6.4 (64.7–94.8)	74.0±7.5(63.3–81.2)	0.006^*

^*Indicate the differences are statistically significant. VRR, Volume reduction ratio; CA, Complete ablation; ICA, Incomplete ablation; RFA, Radiofrequency ablation.

4 Discussion

According to the recent guideline [19], RFA is indicated for both BTNs and inoperable, recurrent thyroid cancers, whereas it is not indicated for follicular neoplasms and primary thyroid cancers because there is no evidence of treatment benefit by RFA in follicular neoplasms and primary thyroid cancers. Although RFA is not the standard procedure, RFA has shown efficacy and safety in the treatment of TNs which may be an alternative to surgery in patients with BTNs [19]. US-guided RFA treatment for BTNs is aimed to control nodule growth and resolve nodule-related clinical problems such as compressive symptoms, cosmetic problem and anxiety about a malignancy. In our study, all BTNs achieved therapeutic success and the mean VRRs of RFA was 81.9% at the 6-month follow-up, which was consistent with the previous studies that the VRRs for BTNs ranged from 75% –97% by using RFA [3, 14], while by using laser ablation (LA) and microwave ablation (MWA), the mean VRRs were 44% –62% and 46% –65% respectively at the 6-month follow-up. In addition, all patients tolerated well and no major complications occurred in the present study. In a Korean multicenter study involving 1459 patients, the complication rate was 3.3% [1]. Voice change after RFA is uncommon (1.02%), which is caused by thermal injury to recurrent laryngeal nerve or vagal nerve. Other complications include pain, skin burn, hematoma, and thyroid function disturbance. Nearly all the complications can resolve spontaneously and do not need additional medication.

On the other hand, Valcavi et al. [23] reported 9% of regrowth by the definition of an increase of nodule volume over initial volume in LA. Lim et al. [17] found that overall regrowth rate was 5.6% in RFA, with regrowth defined as a >50% increase in nodule volume compared with the previous follow-up volume. In the present study, VRRs of ICA nodules were less than CA nodules at the 3- and 6-month follow-up (all P < 0.05). Nodule regrowth often indicates treatment failure and should be avoided, which is generally due to ICA of the target nodule that the un-ablated areas would increase in size in the follow-up since the intranodular blood vessels are not completely destructed. Therefore, to reduce ICA rate at the first time is important to reduce nodule regrowth. Fortunately, the initial treatment response can be evaluated by intra-procedural CEUS, which facilitates quick decision-making regarding the following treatment planning such as re-ablation in the same session or discharge for follow-up.

As revealed by the current study, the factors associated with initial ICA after RFA for BTNs were predominantly solid nodule, nodule close to danger triangle area, nodule close to carotid artery, and peripheral blood flow on color-Doppler US. Previous studies also showed that predominantly cystic nodules showed a significantly better response than predominantly solid nodules after RFA [13]. The solid nodule usually has more content to be ablated since intranodular blood vessels are much more than those in predominantly cystic nodules. Likewise, blood perfusion mediated cooling effect might be more remarkable for predominantly solid nodules in comparison with predominantly cystic nodules since more blood vessels are seen in the predominantly solid nodules. Therefore, for solid nodule, it is necessary to increase power and take more time to achieve CA of the nodule.

For nodule close to danger triangle area or nodule close to carotid artery, ICA might be encountered since the operator is always cautious to ablate the areas adjacent to the critical structures such as nerve and carotid artery. As to nodule close to danger triangle area, trans-isthmic approach is usually used to minimize the heat exposure to the nerve, whereas it may cause un-ablated tissue adjacent to the nerve. In addition, heat-sink effect is obvious for nodule close to carotid artery since the heat can be carried away by the blood flow in the carotid artery [12]. As a consequence, the energy deposit is not enough to destroy these areas and a subsequent ICA is found. In clinical practice, for nodule close to danger triangle area or carotid artery, special maneuver such as hydrodissection technique can be applied. By using hydrodissection technique, fluid mixture of lidocaine and normal saline was injected to separate the thyroid from adjacent critical structures, which serves as a protective thermal barrier to adjacent critical structures and limits damages to these structures. Because of the longitudinal arrangement of the neck muscles and fasciae, injected saline spread rapidly along the muscle plane [13]. Therefore, for those nodules close to danger triangle area and carotid artery, it is necessary to inject sufficient fluid between the critical structures and nodules to ensure enough dissection between them.

Nodules with peripheral blood flow on color Doppler US were also associated with initial ICA. The residual viable tissue was usually seen at the periphery of the nodule and rim-like hyper-enhancement was visualized on CEUS. On the other hand, nodule vascularity on color Doppler US and enhancement extent on CEUS were not identified to be associated factor for ICA in the current study. These facts denoted that the peripheral blood flow other than intranodular blood flow influences the local treatment outcome more obviously. The underlying mechanism might be perfusion-mediated tissue cooling around the BTNs by the peripheral blood flow, which results in rim-like residual viable tissue at the periphery of the nodules [8]. Therefore, for nodules with peripheral blood flow, it should be emphasized to damage the periphery flow firstly.

It was not anticipated that pretreatment nodule volume was not associated with initial ICA in the current study. On the contrary, Baek JH et al. [2] found that RFA was less effective when used to treat TNs >4 cm in diameter. The discordance might be related to different inclusion criteria, thus future study was still necessary to evaluate the impact of nodule volume to ICA.

Three-dimensional contrast-enhanced ultrasound (3D-CEUS) was recently developed and its usefulness was validated in treatment efficacy assessment after RFA of liver tumor, which might provide more information with regard to treatment response evaluation after RFA for BTNs [27]. MWA is also an effective and safe method in treating BTNs and the treatment outcome is comparable with RFA [28]. In addition, irreversible electroporation (IRE) is a new ablation technique that uses ultrashort but strong electric fields to produce permanent nanopores in the cellular membrane, which disrupts cellular homeostasis and ultimately lead to cell death. IRE is perhaps useful for the ablation of BTNs whereas preserves the blood vessel and nerves [18]. Therefore, it is anticipated that IRE might achieve better local treatment efficacy in the future.

There were several limitations in the current study. The case number is relatively small, thus further studies with large case series are needed in the future. Besides, selection bias may exist because of the design of retrospective study. In addition, the operator experience might also be an important factor for ICA and should be evaluated in the future. Finally, other US techniques such as elastography was not used to assess the treatment efficacy after RFA, which should be included in future study.

5 Conclusion

The factors associated with initial ICA after RFA for BTNs are predominantly solid nodule, nodule close to danger triangle area and carotid artery, and peripheral flow on color-Doppler ultrasound after RFA of BTNs. Therefore, attention should be paid to avoid these factors and special maneuvers should be carried out when encountering these factors. CEUS assists quick treatment response evaluation and facilitates subsequent additional RFA and final CA of the nodules. Nodules with CA achieve a better outcome in terms of VRR in comparison with those with ICA.

Footnotes

Acknowledgments

The scientific guarantor of this publication is Hui-Xiong Xu. The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. This work was supported in part by the Shanghai Hospital Development Center (Grants SHDC12014229 and SHDC22015005), the Science and Technology Commission of Shanghai Municipality (Grants 14441900900, 15411969000, and 16411971100), and the National Natural Scientific Foundation of China (Grants 81401417 and 81501475).

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