Papillary thyroid cancer is the most common type of thyroid cancer and typically demonstrates excellent clinical outcomes. However, postoperative recurrence occurs in 9–20% of patients within 30 years . When recurrent thyroid cancers are detected, surgery followed by radioactive iodine therapy is the standard treatment. Repeated operations are sometimes difficult to perform because of severe fibrosis and distortion of the normal tissue planes by scar formation, requiring repeated surgeries that demonstrate a higher rate of complications [2▪]. Furthermore, recurrent small tumors can be difficult to find in the surgical field without ultrasound guidance.
Recently, several studies have reported that ultrasound-guided radiofrequency ablation (RFA) and ethanol ablation can be nonsurgical therapeutic options for recurrent thyroid cancers [2▪,3▪,4▪▪]. These studies have revealed that RFA and ethanol ablation demonstrate several advantages, such as less invasiveness, reduction of morbidity, lower complication rates, the ability to be performed on out-treatment patients, and increased quality of life . In addition, repeated RFA and ethanol ablation do not increase complication rate [3▪,4▪▪,6,7]. In contrast, RFA and ethanol ablation are local tumor control methods, that means invisible tumors on ultrasound cannot be treated by these modalities, and therefore the combination of radioactive iodine therapy and/or external beam radiation therapy could increase the curative rate [3▪,8▪▪].
The aim of this article is to review the current status and challenges of RFA and ethanol ablation for the treatment of recurrent thyroid cancers in patients who cannot undergo surgery, with a focus on the efficacy, safety, and the future direction of these treatment modalities.
Regarding the nonsurgical treatment of recurrent thyroid cancers, the Korean Society of Thyroid Radiology Recommendations has proposed RFA as an alternative to surgery, but it should be limited to patients at high risk of surgery and patients who refuse to undergo repeated surgeries [8▪▪]. These recommendations also suggest that tumor recurrence should be confirmed before treatment by ultrasound-guided fine needle aspiration cytology and/or measurement of the washout thyroglobulin concentration [8▪▪,9].
Detailed treatment strategies for the nonsurgical treatment of recurrent thyroid cancers are not well established; however, two strategies have been suggested: complete ablation of any recurrent thyroid cancers visible on ultrasound [3▪,4▪▪] and conservative management to improve any symptomatic and cosmetic problems [2▪]. To achieve complete ablation of recurrent tumors visible on ultrasound, several studies have suggested that nonsurgical treatment be restricted to patients with three or less recurrent thyroid cancers in the neck and no metastatic tumors beyond the neck at the time of treatment [3▪,4▪▪,6,8▪▪]. Conservative treatment has been applied to treat large recurrent cancers that cause cosmetic and/or symptomatic problems, such as pain, dysphagia, hoarseness, and dyspnea [2▪].
Regarding the use of anesthesia, 1–2% lidocaine is used in most treatment centers without premedication [3▪,5,10]. Lidocaine is applied to the puncture site and soft tissue around the recurrent tumor, and this method is regarded as a simple and effective pain control method. However, Monchik et al. have reported the use of intravenous drugs, a combination of fentanyl citrate (100–400 mcg) and midazolam (1–4 mg), as a possible treatment.
Regarding RFA, a straight internally cooled electrode is typically used [2▪,3▪,5,7,11]. Currently, a modified straight internally cooled electrode is being developed for treating thyroid tumors [2▪,3▪,11–13]. This modified electrode is shorter (7 cm shaft length) and thinner (18–19 gauge) than conventional electrodes and can be used with active tips of various sizes (0.5, 0.7, 1, 1.5 and 2 cm) [13,14]. This thin electrode, especially 19 gauge, can also easily penetrate small metastatic tumors through the surgical scar [3▪]. The size of the electrode is chosen according to the tumor size and status of surrounding danger structures. An electrode with a small active tip (<1 cm) is effective for the treatment of small recurrent tumors or tumors that are close to critical structures [3▪]. In the case of large tumors, 1.5–2 cm active tips have been used [2▪,5,7]. The patient is placed in the supine position with the neck extended. Two grounding pads are attached to both thighs. To prevent unnecessary scar formation the skin is not incised, and to prevent serious hemorrhage the vessels along the approach route should be carefully evaluated. The nerves in the lateral aspect of the neck should also be carefully evaluated. If a metastatic tumor is adjacent to the nerve, the hydrodissection technique is useful for preventing thermal injury. A 5% dextrose solution should be carefully injected between the nerve and the tumor [3▪,7,15]. The moving-shot technique has been used to treat benign thyroid nodules and recurrent thyroid cancers [2▪,3▪,11,13,15–17]. Before starting ablation, the targeted tumor should be divided into multiple conceptual ablation units and RFA performed unit by unit by moving the electrode tip. These conceptual units are smaller at the periphery of the tumor and the portions adjacent to the critical structures (e.g., nerve, trachea, and esophagus) and are larger in the central, safe portion of the tumor. For small tumors, however, the electrode should be fixed to the center of the tumor and not be moved during the procedure. Initially, the electrode tip is positioned in the deepest and most remote conceptual unit of the tumor to enable easy monitoring of the electrode tip without the disturbance caused by microbubbles.
Ablation is started using 10 W of power in the 0.5 cm active tip and 30 W in the 1 cm active tip. If a transient hyperechoic zone does not form at the electrode tip within 5–10 s, the radiofrequency power can be increased in 5–10 W increments up to 30–80 W. If the patient cannot tolerate pain during ablation, lidocaine injection around the tumor can be used to relieve pain. Ablation should be terminated when all conceptual units have changed to transient hyperechoic zones because echogenic microbubble formation during the radiofrequency procedure is regarded as effective ablation [2▪,3▪]. RFA is usually performed on both the metastatic tumors and the surrounding normal tissue in order to prevent local recurrence (Fig. 1) [3▪]. Dupuy et al. also reported the use of internally cooled electrodes but they used somewhat different techniques. Regarding their technique, internal cooling is only used for masses more than 1 cm across the greatest dimension. Otherwise, the electrode tip temperature should be maintained at 90°C for 2 min without internal cooling. If the temperature within the mass is less than 50°C (the cytotoxic threshold), then additional RF treatments should be performed at the new electrode position. Assessing the treatment adequacy of cystic lymph nodes is more difficult than solid tumor because their cystic portion rapidly disappears following treatment. However, cystic tumor also seems to be effectively treated by RFA . After ablation, the operator should check any discomfort or complications and the patient should be observed for 1–2 h at the hospital.
Regarding ethanol ablation, 3–4 cm long 22–25 gauge needles have been used that are attached to a 1 ml syringe containing 95–99.9% ethanol [4▪▪,7,18,19]. After administering local anesthesia, 0.1–1 ml ethanol (per one session) is injected from the deep and peripheral portion of the recurrent thyroid cancer to the central area. Immediately following the injection of ethanol, the injected area becomes echogenic. After a short time, typically less than 1 min, the echogenic area will decrease, allowing better visualization of the needle. The needle is then repositioned to the untreated vascular area using color Doppler ultrasound, and ethanol injections are continued until the entire lymph node is adequately treated. If leakage to the outside of the lesion is detected on ultrasound or if the patient complains of severe pain, the ethanol injections are immediately terminated. When the entire tumor changed echogenically, ethanol ablation is terminated .
During the follow-up period, the indications for repeated RFA or ethanol ablation include the presence of power Doppler signals despite a reduction in tumor size [3▪,4▪▪,6], tumor volume reduction less than 50% , and the presence of residual tumor tissue on fine-needle aspiration cytology [4▪▪,5,19]. The complete treatment of a large tumor is usually impossible in a single session. Dupuy et al. treated a 5 cm recurrent tumor over the course of five sessions using RFA, and Baek et al.[3▪] treated a 2.8 cm tumor over two sessions using RFA. Lewis et al. also suggested that the undertreated portion can usually be detected using Doppler ultrasound in patients with large recurrent cancers that are deeply situated.
Efficacy is evaluated by the reduction in the tumor volume [(initial volume – final volume) × 100/initial volume] [11,13,16], the therapeutic success rate (volume reduction >50%) , complete disappearance of the treated tumor, the serum thyroglobulin concentration, tumor perfusion, and changes in the echogenicity of the treated tumor [8▪▪].
Following RFA, several investigators have reported a mean volume reduction of 56–93% [2▪,3▪], complete disappearance of 42–58.2% of tumors [3▪,5,7], therapeutic success rates of 75–91.6% [3▪,5,7], improvement of symptoms in 64% of patients [2▪], and a decrease in the serum thyroglobulin concentration in the majority of patients [2▪,3▪,5,7]. However, long-term follow-up data have not been published. The reduction in the mean tumor volume following ethanol ablation has been reported to range from 37.5 to 96%, complete disappearance has been reported for 31–65% of treated tumors [4▪▪,6,18,19], therapeutic success rates of 70.8–98% [6,18], and a decreased serum thyroglobulin concentration has also been reported [4▪▪,7,19]. Because of excellent local tumor ablation, Heilo et al.[4▪▪] suggested that ethanol ablation could replace ‘berry picking’ surgery.
The efficacy of RFA is similar or somewhat superior to that of ethanol ablation, requiring fewer treatment sessions (mean: 1.2 sessions; range, 1–6) [3▪,5,7] than ethanol ablation (mean: 2.0–2.1 sessions; range: 1–6) [4▪▪,6,18,19]. Lewis et al. also suggested that RFA also has an advantage in terms of the number of treatment sessions required to treat recurrent thyroid cancers in comparison with ethanol ablation.
For evaluation of efficacy ultrasound and computed tomography are key imaging modalities [8▪▪]. During the follow-up period, well treated tumors demonstrate increased echogenicity in the tumor and surrounding soft tissue, loss of intratumoral color Doppler signals, and decreased tumor size on ultrasound [3▪,7]. Incomplete treatment has been reported due to intractable pain, major vessel encasement, severe calcification [2▪], and the tumor being located close to the vagus nerve [3▪]. Local tumor recurrence has been reported to occur at a rate of 0–25% following RFA [3▪,5,7] and 3.2–33% following ethanol ablation [4▪▪,7,18,19].
Following RFA and ethanol ablation, various complications have been reported, including discomfort, pain, skin burn, and changes in voice (Table 1) [2▪,3▪,4▪▪,5–7,18,19]. The most common complications are discomfort and pain at the treatment site. The majority of patients complain of discomfort and pain during ablation. Pain sometimes radiates to the jaw and chest , but is usually resolved within several minutes to hours following the procedure. To relieve pain during ablation, the ablation power is reduced or stopped and/or local anesthesia is administered deep into the tumor or surrounding tissue [17–19]. In addition, during ethanol ablation, pain is most likely related to localized leakage of the injected ethanol into the surrounding soft tissue. Pain does not disturb the RFA or ethanol ablation procedures in most patients [4▪▪,5–7,14,18,19], but Park et al.[2▪] reported the inability to complete RFA in five patients due to intolerable pain.
Changes in one's voice are some of the most serious complications that can occur following RFA or ethanol ablation. All voice complications happen during the treatment of central neck lesions. Changes in voice have been reported in 7% (three of 45) of RFA patients [3▪,5,7] and 2.4% (three of 126) of ethanol ablation patients [6,7,19]. Three patients with voice changes following ethanol ablation were transient and recovered within 3 h to 7 days. Three patients with voice changes following RFA did not fully recover during their follow-up periods. RFA produces a larger zone of tumor destruction than ethanol ablation; therefore, RFA is more likely to cause permanent injury to the adjacent nerves. This complication can be overcome by hydrodissection technique [3▪,7,15].
Within the lateral neck, the vagus nerve is one of the most dangerous structures. The vagus nerve is located within the carotid sheath, usually posterolateral to the common carotid artery and posteromedial to the internal jugular vein, and it is easily detected on ultrasound [3▪,10,17,21]. To avoid thermal injury to the vagus nerve, the operators should be aware of the location of the vagus nerve and its variations on ultrasound [10,21]. During the procedure, use of the hydrodissection technique and verbal communication may minimize nerve injury [3▪]. As mentioned earlier, in order to prevent injury to the nerve or other danger structures, the moving-shot technique, which uses a small active tip (<1 cm), and the hydrodissection technique are helpful [8▪▪]. When the operators use the hydrodissection technique, the continuous infusion of fluid is necessary because injected fluid spreads gradually along the muscle plane of the neck. Another strategy that prevents thermal injury is the use of a unidirectional ablation electrode [3▪,22]. This electrode was used to modify the direction of the ablation and produce asymmetrical half-moon-shaped ablation zones in an ex-vivo study ; however, no human studies have been reported that used this electrode.
Skin burns have been observed following the use of RFA to treat liver tumors at the sites of electrode puncture and pad attachment [23,24]. Skin burns also have been reported at the electrode insertion site during the use of RFA to treat recurrent thyroid cancers [2▪,5,7]. However, there have been no reports of skin burns at the site of pad attachment because the use of RFA energy for the treatment of recurrent thyroid cancers is lower than that of liver. The frequent application of an ice bag  or the injection of fluid between the tumor and skin  during the procedure may prevent skin burn.
Serious complications, such as injury to the esophagus, trachea, or other nerves (e.g., spinal accessory, sympathetic ganglion, phrenic, and brachial plexus nerves), have not been reported following the treatment of recurrent thyroid cancers, which can be located near these structures. To prevent these serious complications, the operators should be aware of the anatomy of the neck and always trace the electrode tip during the procedure using ultrasound.
RFA and ethanol ablation are possible alternatives for the treatment of recurrent thyroid cancers in patients at high risk of surgery or those who refuse repeated surgeries. RFA is slightly superior to ethanol ablation in terms of efficacy, mean number of treatment sessions required, and the extent of the ablation zone. However, RFA demonstrates a higher tendency and severity of voice complications than ethanol ablation for the treatment of central neck lesions. To minimize these complications, the operators should be aware of the various possible complications that could present as well as the preventive techniques that are available.
The authors alone are responsible for the content and writing of this article.
Conflicts of interest
None of the authors have any to disclose.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 100).
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