Role of ultrasound in the assessment of percutaneous laser ablation of cervical metastatic lymph nodes from thyroid carcinoma

Abstract

Background

Few studies have examined the feasibility and efficiency of performing ultrasound and contrast-enhanced ultrasound (CEUS) after percutaneous laser ablation (PLA) of cervical metastatic lymph nodes from thyroid cancer.

Purpose

To investigate and describe the use of conventional ultrasound and CEUS in evaluating PLA of metastatic lymph nodes.

Material and Methods

PLA was performed in a small, prospective, observational study of 21 metastatic lymph nodes in 17 thyroid cancer patients who underwent radical thyroid resection. CEUS was conducted prior to PLA and 1 h and seven days after ablation. Conventional ultrasound examination of all nodes was performed during follow-up after ablation. We observed contrast agent perfusion in the lymph nodes, calculated perfusion defect volumes using CEUS and determined the rates of reduction for metastatic lymph nodes for a mean duration of 17.86 ± 4.704 months (range = 12–27 months).

Results

CEUS demonstrated that the perfusion defect volume was larger on day 7 than on day 1 post-ablation in 47% of the ablated nodes. Compared to the largest diameters and volumes pre-PLA, the corresponding post-PLA values significantly decreased (P < 0.05 versus baseline). No statistically significant change in thyroglobulin (Tg) levels before and after PLA was observed in this study (P > 0.05 versus baseline).

Conclusion

CEUS can be effectively used to distinguish the margins of ablated regions, assess the accuracy of PLA, and monitor short-term changes in necrotic areas. However, long-term follow-up assessments of the curative effect of PLA will predominantly rely on conventional ultrasonography.

Keywords

Percutaneous laser ultrasound intravenous contrast agents lymphatic metastases

Introduction

The spread of papillary thyroid cancer cells primarily occurs through the lymphatic system. In addition to surgery and ¹³¹I administration for treating metastatic lymph nodes, minimally invasive ablation methods (percutaneous ethanol injection (1,2), percutaneous laser ablation (PLA) (3,4), microwave ablation (5,6), and radiofrequency ablation (7 –10) are available. Due to its high precision and small degree of injury, ultrasound-guided PLA has recently been used to treat cervical metastatic lymph nodes from papillary thyroid cancer (3,4). However, the efficacy of any therapeutic procedure should be assessed. We believe that two-dimensional high-frequency ultrasound and contrast-enhanced ultrasound (CEUS) can be used to evaluate this procedure. The former modality is the most common diagnostic method for assessing superficial organs, whereas the latter modality can increase the contrast of lesions relative to the surrounding tissues by enhancing ultrasonic echoes in the microvasculature (11,12). Both methods have the potential to play vital roles in the assessment of therapeutic effectiveness. Thyroglobulin (Tg) is often used to monitor the recurrence of papillary thyroid carcinoma (13,14); therefore, changes in serum Tg levels before and after PLA should also be evaluated. Increased serum Tg levels after ¹³¹I treatment are indicative of recurrence or lymphatic metastasis (15,16). The aim of this study was to investigate and describe the use of conventional ultrasound and CEUS combined with serum Tg measurements for the assessment of PLA treatment of cervical metastatic lymph node metastases from papillary thyroid cancer.

Material and Methods

Patients

This study was conducted according to the guidelines of the World Medical Association Declaration of Helsinki and was approved by the ethical committee of our hospital. Between January 2014 and March 2015, all patients included in the study satisfied the following criteria: (i) three or fewer recurrent lesions and no evidence of distant metastases; (ii) maximum lymph node diameter of less than 1.5 cm, which was adopted based on the limited effective range of laser ablation; (iii) no massive calcifications (larger than 2 mm) capable of blocking energy transmission; (iv) the patient was a poor candidate for surgery (e.g. high risk for general anesthesia or repeated neck dissection) and/or chose not to undergo surgery; and (v) the patient underwent at least one ¹³¹I treatment, and ¹³¹I whole-body scintigraphy showed that iodine uptake did not occur in any lesions. We excluded patients with lesions larger than 1.5 cm and with more than three lesions and in cases of non-cervical metastasis and patients without a firm subjective intention to participate in the study. Twenty-one metastatic lymph nodes in 17 patients were confirmed by ultrasound-guided fine needle aspiration cytology (FNAC) before PLA. Eighteen lesions were ablated once and three were ablated twice because of incomplete initial ablation. All patients were treated with levothyroxine suppression therapy and growth inhibition of thyroid cancer cells was achieved with Euthyrox (Merck KGaA, Darmstadt, Germany). The study duration was from the day of the ablative endpoint until March 2016.

PLA

Every patient was informed of the relevant risks and possible complications of PLA and provided written informed consent before undergoing therapy. The laser ablation apparatus was an EchoLaser type X4 (Esaote Company, Florence, Italy) with a fiber diameter of 300 µm and radiates Nd:YAG laser light at a wavelength of 1064 nm. All patients underwent conventional local disinfection. After providing local anesthesia with 2% lidocaine, the operator injected isolation fluid containing 2% lidocaine and saline solution at a 1:8 dilution into the interstitial space to isolate important nerves and vessels. The operator then introduced a 21-gauge needle into the target lymph node, removed the needle core, inserted an optical fiber, and backed out the needle tip approximately 5 mm so that the fiber tip remained just in contact with the lymph node. The laser was then activated to begin treatment. With the release of energy following laser activation, a gradually expanding hyperechoic gasification zone formed around the fiber tip. The treatment endpoint was the moment when a strong echo completely enveloped and exceeded the boundaries of the lymph node. All of the above processes were performed under real-time ultrasound guidance. All ultrasonographic examinations and ablative procedures were carried out by two radiologists with more than five years of experience performing interventional therapy.

CEUS and outcome assessment

Every patient was informed of the relevant risks of CEUS and provided written informed consent before the examination. The apparatus used was an Esaote MyLab 90-color Doppler ultrasound instrument (Esaote Company) equipped with an LA 522 high-frequency linear probe that uses contrast-tuned imaging technology (CnTI). The mechanical index was under 0.10. SonoVue contrast medium was used (59 mg of powder, Bracco Suisse SA, Plan-Les-Ouates, Switzerland). The contrast-medium powder was dissolved in normal saline prior to intravenous injection. Before CEUS was performed, the focus was set to the deep edge of the lesion, and the gain was regulated to suppress soft-tissue echoes while retaining the contours of the lymph node, trachea, and vascular wall visible. The lymph node region with the largest diameter was continually scanned while using the carotid and subclavian arteries as references. The ultrasonic probe was kept stationary throughout the process. Meanwhile, the assistant injected 5 mL of saline into a vial of sulfur hexafluoride (SF6) and mixed the sample until the powder was well dispersed. At the beginning of CEUS, a 2.5-mL bolus of contrast agent was injected into a superficial vein and flushed with 5 mL of normal saline. Image data were recorded at the beginning of injection, and recording was stopped when most of the contrast agent had receded from the lymph node.

Each lesion was evaluated via CEUS prior to PLA and again 1 h and seven days after the treatment. The evaluation included an assessment of perfusion and the calculation of defect volumes. The perfusion levels of post-ablative lymph nodes were classified as homogeneous perfusion, inhomogeneous perfusion (combination of high, moderate, or low perfusion areas in one lymph node simultaneously), or no perfusion (almost no contrast agent entering the lymph node). Perfusion defect volumes were calculated after PLA using the ellipsoid volume formula (ellipsoid volume = 0.523 × width × length × height).

Conventional ultrasound and follow-up

Before and after PLA, patients underwent gray-scale ultrasound and color Doppler examinations using Esaote MyLab 90 and Esaote Twice color Doppler ultrasound instruments equipped with an LA 523 high-frequency linear probe (Esaote). Prior to PLA, a comprehensive neck scan was performed to ensure that there were no other potential metastatic lymph nodes. The scan was concentrated on the target lymph node, with observations including node location, number, size, shape, border, internal echo, and blood flow pattern. Color Doppler ultrasound showed three levels of blood supply, classified as abundant (more than half of the area in the maximum cross-section), medium (about half of the area in the maximum cross-section), or poor (less than half of the area in the maximum cross-section). Measurements of the nodes included the long, short, and transverse diameter, which were used to calculate node volume.

During PLA, conventional ultrasound (including gray-scale and color Doppler ultrasound) was used to guide the path of the introducer needle and monitor the process of liquid injection and lymph node ablation.

One hour after PLA, gray-scale and color Doppler ultrasound were used to estimate the occurrence of complications, such as local edema and the development of hematomas, and to observe changes in the ablated lymph node.

Follow-up with conventional ultrasound was performed 1 h, seven days and one, three, six, and 12 months after PLA to determine changes in the shrinkage rates of the ablated lymph nodes. The volumes of all lymph nodes were calculated during the follow-up period using the ellipsoid volume formula. Reduction rate was defined as the percentage (%) reduction of the metastatic lymph node after PLA, with the reduction rate = (lesion volume before PLA - lesion volume at the end of follow-up)/(lesion volume before PLA). Serum was collected for Tg assays before ablation and 1–3 months after treatment.

Statistical analysis

Data were analyzed using IBM SPSS Statistics 19 (SPSS IBM, Armonk, NY, USA). The largest nodule diameter and volume and highest serum Tg level recorded post-PLA were compared with the corresponding values measured pretreatment using paired sample t-test. Data were reported as the mean ± standard deviation (SD), and the level of significance was defined as P < 0.05.

Results

In this study, 15/17 (88.24%) patients had a solitary metastatic node discovered by ultrasound. PLA was performed on 21 metastatic lymph nodes (LN4, 5, and 6 belonged to the fourth patient; LN18, 19, and 20 belonged to the 16th patient) from thyroid carcinoma in 17 patients (14 women, three men; age range = 23–59 years; mean age = 43.94 ± 10.50 years). Repeated treatment was performed in three cases (LN1, LN9, and LN13) in which the initial treatment appeared to be incomplete based on the observation of inhomogeneous perfusion during CEUS after PLA (Suppl. Table 1). All three cases underwent a second PLA treatment and had no evidence of recurrence at the end of the follow-up period (Fig. 1).

Prior to PLA, the perfusion of all metastatic lymph nodes was determined to be homogeneous. Color Doppler ultrasound showed an abundant, medium, and poor blood supply in 5/21 (23.80%), 14/21 (66.67%), and 2/21 (9.52%) of the nodes, respectively. The mean largest diameter was 0.738 ± 0.261 cm (range = 0.41–1.29 cm), and the average initial volume was 0.110 ± 0.125 mL (range = 0.019–0.536 mL).

Within 1 h after PLA, color Doppler examination demonstrated the absence of vascular signals in the treated area. Due to gasification and tissue edema, the margins of the ablated regions could not be clearly displayed using conventional ultrasound, including gray-scale ultrasound and color Doppler ultrasound. With the help of CEUS, every ablated area was found to have a relatively clear boundary, providing an intuitive understanding of the ablation range. In 18/21 (85.7%) of the ablated areas, CEUS showed no perfusion, and the perfusion defect volumes that we calculated were not less than the initial volumes determined with gray-scale ultrasound. However, the contrast agent entered three ablated lymph nodes, which were therefore considered to have been incompletely ablated.

On the seventh day after treatment, the margins of 5/21 (23.81%) ablated areas could still not be clearly observed via conventional ultrasound, whereas these areas showed a relatively clear boundary when examined using CEUS. We also found that the perfusion defect volumes of 10/21 (47.6%) of the post-ablative areas were larger than the volumes 1 h after PLA (Fig. 2), and the mean increased volume was 0.991 ± 0.205 mL. The volumes of the other ten areas were smaller than those measured 1 h after PLA, and the mean decreased volume was 0.548 ± 0.488 mL. Only one post-ablative area remained the same.

After long-term follow-up, all lesions disappeared, and there were no recurrences by the end of the follow-up period. The mean follow-up time was 17.86 ± 4.704 months (range = 12–27 months). No lymph nodes were detectable after long-term follow-up, so the reduction rate of all lesions was 100%. Comparisons of measurements before and after PLA showed that the changes in the largest diameters and lymph node volumes were statistically significant (P < 0.05) (Table 1). However, Tg levels were not significantly higher before PLA than at last follow-up visit (P > 0.05). At the end of the follow-up period, all ablated lymph nodes were smaller than they were before ablation. None could be observed via ultrasound and they were therefore considered to have been completely ablated. Because the lymph nodes had disappeared completely by the one-year follow-up, additional FNAC was not necessary.

Table 1.

Outcomes following percutaneous laser ablation of cervical metastatic lymph nodes from thyroid carcinoma.

Measurement	Before PLA (mean ± SD)	Last follow-up visit (mean ± SD)	P value
Largest diameter (mm)	0.738 ± 0.261	0.000 ± 0.000	0.000
Volume (cm³)	0.110 ± 0.125	0.000 ± 0.000	0.001
Serum Tg level (ng/ml)	0.863 ± 1.904	0.310 ± 0.746	0.102

PLA, percutaneous laser ablation; SD, standard deviation; Tg, thyroglobulin.

Regarding complications, we found no bleeding or local hematomas during treatment. However, some complications occurred. One patient experienced hoarseness and cough caused by nerve injury after PLA. Ultrasonic imaging identified an ablated area that had clear edema surrounding an ablated lymph node at 1 h after PLA. The patient recovered within three months without treatment.

Discussion

Conventional ultrasound, including gray-scale ultrasound and color Doppler ultrasound, plays a vital role in the entire PLA process (17,18). Prior to PLA in the current study, gray-scale ultrasound was performed to measure three diameters to calculate lymph node volume. Color Doppler ultrasound was used to estimate the blood supply. The entire PLA process, including determining the locations of metastatic lymph nodes, guiding the insertion of introducer needles, and observing the areas producing strong echoes during energy release, was monitored via ultrasound. In this way, we were able to control the operation with confidence and flexibility (Fig. 3). We assessed the occurrence of complications with the aid of ultrasound and found that patient 14 had edema surrounding the post-ablative area. This edema could cause hoarseness by compressing the recurrent laryngeal nerve. After ablation, we used color Doppler to make preliminary determinations regarding whether the ablation areas were sufficient to encircle the primary lesion.

CEUS assessment of thermal ablation is a feasible and effective tool for estimating tumor ablation and is accepted as a viable follow-up method (3,7 –9,19 –22). The mechanism by which CEUS works depends on an enhanced ultrasonic echo via an enhanced backscatter signal caused by the flow of microbubble contrast medium in the microvasculature (11). The mean elimination half-life of SonoVue is 12 min. Fifteen minutes after injection, nearly all of the SF6 bubbles were discharged. Therefore, re-injection of the contrast agent 1–2 h before and after PLA did not influence the results. In this study, when we observed target lesions before PLA, color Doppler ultrasound was used to estimate the blood supply. However, color Doppler had some limitations in detecting small blood vessels and low-velocity blood flow. For this reason, CEUS was primarily used to assess blood supply in this study. The objective was to establish contrast values that could be compared to the results from reexamination after treatment to ensure the range and accuracy of ablation. As previously reported, CEUS has high specificity, sensitivity, and accuracy and can provide valuable information in assessing ablative effects in treating hepatocellular carcinoma (8,9,20,21) and renal tumors (7,19,22). In the present study, the margins of some ablated areas were not initially clear; however, the boundaries became immediately evident with the help of CEUS. We could accurately judge the positions of necrotic areas and calculate the corresponding volumes. The use of CEUS helped identify three cases of incomplete ablation showing inhomogeneous perfusion. These findings indicated incomplete ablation and the need for a second treatment.

The CEUS results showed that several perfusion defect volumes were larger on the seventh day than those measured 1 h after PLA. These results indicate that the defect volume after 1 h may not represent the final necrotic range of PLA and that a short-term re-evaluation of CEUS results is needed. A likely reason for this difference may be the further expansion of necrotic areas because the outermost layer of the ablated tissues showed hematomas and edema after thermal ablation, likely followed by aggregation of inflammatory cells and secreted mediators of inflammation. This could in turn increase platelet aggregation and accelerate the release of inflammatory cytokines and tumor necrosis factor (23). These actions initiate the blood clotting cascade and promote microthrombus formation, which could exacerbate tissue ischemia and further expand the necrotic area (24). After several days, no enlargements in lymph node perfusion defects were observed in our study. We hypothesized that with the regression of inflammation, a new capillary network gradually formed under the influence of fibroblasts, the extracellular matrix, and various cellular factors. With the elimination of edema and inflammation, the volume of the ablative area would be expected to gradually shrink.

After PLA, the largest diameter and volume changed significantly relative to the corresponding pre-PLA values. Therefore, during long-term follow-up, the final estimation of the treatment effect predominantly relied on conventional ultrasound because of its advantages in the assessment of superficial organs, including the ability to obtain high-resolution data and perform real-time examinations, as well as its convenience for use in follow-up. Although the serum Tg levels of some patients decreased after treatment in this study, no statistically significant differences were observed. This indicates that effective assessment of PLA cannot rely on Tg measurements alone because of the influence of various factors, such as Euthyrox, ¹³¹I treatment and the number of lesions.

We believe that the findings that indicate a successful ablation include the absence of perfusion, as determined by CEUS, and unequivocal lymph node shrinkage or disappearance within a year compared with the initial assessment. Therefore, if conventional ultrasound reveals the persistent presence of blood vessel signals from within lymph nodes or if homogeneous or inhomogeneous perfusion is determined via CEUS, metastasis should be suspected. If node reduction is not apparent after one year, FNAC can be performed to rule out recurrence.

This study had several limitations. First, as the sample size is small, a large prospective study is recommended to validate our observations. Second, the ellipsoidal formula used for determining lymph node and ablative volume is an approximation and may have been inaccurate due to shape changes in necrotic areas during follow-up. Third, this study did not provide a comparison with other therapeutic regimens.

In conclusion, CEUS may play a vital role in assessing the short-term efficacy of PLA for cervical metastatic lymph nodes from thyroid cancer. Conventional ultrasound can be used to guide the entire PLA process and is technically effective and feasible for long-term PLA follow-up.

Footnotes

Acknowledgments

The authors thank all those who helped during the period of doing the research and writing this paper. They also thank Yi Cao, Dan Zhou, and Yating Xie, who are assistant nurses in the course of treatment in the department. Without their help, we could not successfully accomplish the whole process. They thank the engineers of Esaote Company who helped with technique support. Lastly, they also thank Kimberly Yasutis who works for American Journal Expert(AJE) and supplied writing assistance.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Capacity building project of auxiliary department (Ultrasonic Medicine), clinical science and technology innovation project from Shanghai Shen Kang Hospital Development Center. The project number is SHDC22015006. The project name is Clinical Study of Ultrasound Guided Percutaneous Laser Ablation of Cervical Metastatic Lymph Nodes from Thyroid Carcinoma. The authors also received the following funding: Science and technology commission foundation of Shanghai. The project number is 14411961000. The project name is Clinical study of ultrasound-guided percutaneous laser ablation of papillary thyroid microcarcinoma.

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