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Advances in nonsurgical treatment of benign thyroid nodules
Eun Ju Ha1 & Jung Hwan Baek*,2
ABSTRACT: Ethanol ablation has traditionally been used for treatment of cystic thyroid nodules. Laser ablation and radiofrequency ablation were introduced later and used for treatment of solid thyroid nodules. However, how to select the best treatment modality among the different techniques has, so far, not been determined and causes confusion in clinical practice. Therefore, the necessity for a proper guideline regarding the choice of the preferable treatment modality has been suggested as the use of nonsurgical treatment for benign thyroid nodules has been increasing. This article provides an up-to-date review of nonsurgical treatment of benign thyroid nodules focusing on how to select the best treatment modality according to the composition of thyroid nodules based on the clinical evidence. Thyroid nodules are common in clinical practice. The percentage of benign nodules among all thyroid nodules has been reported to be 85–95%, depending on age, gender, radiation exposure history, family history and other factors in published studies [1–3] . Although most thyroid nodules are benign and treatment is unnecessary, treatment is required for the patients with cosmetic or symptomatic problems  . Surgery or radioiodine therapy has been used for these patients; however, they have several drawbacks [5,6] . For cystic and predominantly cystic thyroid nodules, ethanol ablation (EA) has traditionally been used and has yielded good results [7,8] . The drawbacks of EA for solid nodules have been suggested that uneven distribution of ethanol inside the solid nodule and leakage of ethanol outside the thyroid gland [8,9] . Therefore, the efficacy of EA decreased when the proportion of the solid component and the vascularity increased  . The volume reduction of EA for solid nodules has been reported to be approximately 50% with the mean number of treatment sessions to be 1–1.9 [10–12] . Higher volume reduction rates were reported in a few studies (69–70%); however, their mean treatment sessions were much higher (5–7.4) [13,14] . Therefore, EA is not recommended for solid thyroid nodules any more  . To overcome these drawbacks of EA, thermal ablation techniques, such as laser ablation (LA) and radiofrequency ablation (RFA), have been suggested [4,16–20] . Although these thermal ablation techniques are effective in both cystic and solid thyroid nodules, there have been no guidelines regarding the choice of the preferable treatment modality. Recent studies suggested treatment strategies according to the proportion of the solid component [21–24] . Therefore, the goal of this article is to determine how to select the best treatment modality among the different techniques currently available (EA, LA and RFA) based on the clinical evidence.
• ethanol ablation • laser ablation • radiofrequency ablation • thyroid nodule • ultrasonography
Department of Radiology, Ajou University School of Medicine, Wonchon-Dong, Yeongtong-Gu, Suwon 443–380, South Korea Department of Radiology & Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-Gil, Songpa-Gu, Seoul 138–736, South Korea *Author for correspondence: Tel.: +82 2 3010 4348; Fax: +82 2 476 0090; [email protected]
10.2217/FON.14.59 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(8), 1399–1405
Special Report Ha & Baek Indications & follow-up Nonsurgical treatments such as EA, LA and RFA are a good alternative to surgery in patients with benign thyroid nodules. Thyroid nodules should be confirmed as benign by at least two separate ultrasonography (US)-guided fine needle aspiration and/or core needle biopsy prior to nonsurgical treatment  . US examination is important for the characterization of nodules and the selection of treatment modality according to their composition. Thyroid nodules with malignant US features should be carefully treated even though there are benign cytohistologic results  , and any nodule that is suspected to be primary thyroid cancer is contraindicated for the procedures. After nonsurgical treatment, patients are recommended to be followed-up at 1–2, 6 and 12 months, as well as every 6–12-month intervals thereafter, depending on the status of the treated nodules. Additional treatments may be indicated in patients with incompletely resolved clinical concerns or if a viable growing portion of the nodule is detected on US. Procedures ●●Ethanol ablation
High concentration (95–99%) of ethanol has been used to improve the efficacy. The needle puncture is recommended through the isthmus of thyroid gland. Sufficient amount of normal thyroid parenchyma (isthmus) could prevent leakage of ethanol during the procedure, which is a cause of pain and perithyroidal fibrosis  . A 16–21-gauge needle is inserted into the nodule through an isthmus. After the tip of needle is placed into the center of the cyst, the internal fluid is aspirated to the maximum extent possible, followed by injection of ethanol into the cyst. If the cystic fluid is colloid, it can be aspirated by a large bore needle (16 gauge) attached to a 20-ml syringe. Normal saline irrigation is then used to remove colloid attached to the cyst wall, after which ethanol is injected [8,23] . The amount of ethanol is usually more than 50% of that of the aspirated fluid volume. After 2 min of ethanol retention with the needle in place, the injected ethanol is recommended to be removed completely and then the needle is to be removed as well  . ●●Laser ablation
The f lat-tip technique has been suggested for LA  . It is based on insertion of a laser fiber through the sheath of a 21-gauge needle,
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with 5 mm of the bare fiber being in direct contact with thyroid tissue  . One to four needles are placed along the longitudinal axis (cranio–caudal direction), with the distance of each fibers being 1 cm, and forming an ellipsoidal shape matching that of the thyroid nodules [26,27] . The initial ablation starts at 1.0 cm from the caudal portion of the thyroid nodule. A transient hyperechoic zone gradually increases over time and then coalescence between fibers is observed. At this time, the operator pullbacks the fibers in 1.0-cm increments. Additional doses of laser energy are administered at each step until the fibers are 5 mm away from the cranial portion of the nodule. The number of fibers, that of pullbacks and the total energy delivered, are tailored to nodule volume and to the ellipsoidal shape that characterizes such nodules  . ●●Radiofrequency ablation
The Korean Society of Thyroid Radiology has suggested recommendations of thyroid RFA. In the recommendations, a ‘trans-isthmic approach’ and a ‘moving shot technique’ have been suggested for a safe and effective RFA  . A modified, straight-type, internally cooled electrode has been proposed as a suitable device of moving shot technique [26,28] . The Korean Society of Thyroid Radiology recommendations does not recommend the sedatives before or during the ablation since the early detection of complications is impossible in patients under deep sedation, which disturbs communication  . With the trans-isthmic approach, the electrode through sufficient thyroid parenchyma could prevent change in the electrode position when patients are swallowing or talking and also prevent leakage of ablated hot fluid outside the thyroid gland  . The moving shot technique is proposed as an alternative to the fixed electrode technique, which has been used to treat hepatoma. With the moving shot technique, multiple small conceptual ablation units are ablated unit by unit by moving the electrode tip. The tip is initially positioned in the deepest and most remote portion of the nodule, after which it is moved backward to the superficial portion of the nodule so as to prevent visual disturbance caused by transient hyperechoic zones  . The decision of radiofrequency power and size of active tip is depending on the size and the internal characteristics of the targeting nodules. With 1 cm active tip, ablation starts with
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Advances in nonsurgical treatment of benign thyroid nodules 30–50 W of radiofrequency power. If a transient hyperechoic zone does not appear within 5–10 s, radiofrequency power is increased in 10-W increments, to a maximum of 120 W. The RFA is finished when entire nodules have become transient hyperechoic zones  . Cystic thyroid nodules In cystic thyroid nodules, EA has been proposed as the first-line treatment. The mean volume reduction range following treatment is 85–98.5% [30–34] . Recently, in a large study population, RFA also offered promising results for the treatment of cystic thyroid nodules, with a mean volume reduction ratio of 90% seen at the 12-month follow-up  . There have been two published studies which compared the efficacy of EA with RFA for treating benign cystic thyroid nodules – that is, one retrospective study and one randomized controlled trial [23,24] . In the retrospective study, Sung et al. attempted to evaluate the optimal treatment modality for cystic thyroid nodules by enrolling 36 study patients for EA and 21 for RFA  . In this study, additional treatment was used when the cystic portion was greater than 1 ml in volume or if the patient’s symptoms or cosmetic problems had not been completely resolved. There was no significant difference in the efficacy of EA and RFA in terms of the mean volume reduction, therapeutic success rate (volume reduction >50%) or improvement of cosmetic and/or symptomatic problems. There were also no major complications in either group. However, as the number of treatment sessions was fewer for EA (1.2 vs 1.7; p < 0.03), they concluded that EA is superior to RFA in terms of the need for fewer treatment sessions and its cost–effectiveness. Therefore, EA may be the first-line treatment for cystic thyroid nodules. These results were verified by a single-session treatment, noninferiority trial  . If the results of EA are noninferior to those of RFA, EA could become the first-line treatment as it is easy, simple and is an inexpensive treatment modality. A total of 50 patients, each with a single cystic thyroid nodule, were randomly assigned to undergo EA (25 patients) or RFA (25 patients). The noninferiority margin was chosen as -8% (EA minus RFA) based on the fact that previous studies demonstrated that the interobserver measurement variation of thyroid nodules was 5–7% [12,35–36] . These results indicate that EA is not only noninferior, but is also superior to RFA;
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therefore, EA can be used as the first-line treatment for cystic thyroid nodules. These results may also be useful in order to avoid expensive clinical trials or treatment modalities for patients with symptomatic, benign, cystic thyroid nodules which can be successfully managed using the simpler EA method (Table 1)  . Predominantly cystic thyroid nodules In predominantly cystic thyroid nodules, EA has been used as the first-line treatment modality; however, recurrence has been reported in patients following EA [21,22] . The solid component with increased vascularity has been suggested as the main cause of recurrence after EA  . Lee et al. suggested in their retrospective study that the recurrence rate is higher in predominantly cystic nodules than in cystic nodules  . Kim et al. also suggested that predominantly cystic nodules showed a higher recurrence rate than cystic nodules as the solid component and vascularity were the main causes of recurrence  . Lee et al. first reported that in patients with incompletely resolved clinical symptoms following EA, RFA is an effective and safe treatment modality for the next treatment step as the mean volume reduction ratio was 92% 6 months after EA–RFA combination therapy  . In their retrospective study, they suggested that this step-by-step treatment – that is, EA followed by RFA, is an effective treatment modality for predominantly cystic thyroid nodules. Jang et al.  prospectively verified the results of the retrospective study of Lee et al.  . Jang et al. also confirmed that the amount of the solid component was an independent factor for recurrence and that the recurrence rate increased significantly when the solid component was more than 20% of the total volume of predominantly cystic thyroid nodules. The recurrence rate in their study was 33%, and they also performed RFA for these patients. Their results were promising using this step-by-step management – that is, EA followed by RFA. The mean volume reduction ratio in this study was comparable with that of the previous retrospective study of Lee et al. (92 vs 91%) [21,22] . Jang et al. concluded that step-by-step treatment – that is, EA–RFA combination therapy, for predominantly cystic thyroid nodules is an effective and practical treatment strategy. Although EA–RFA combination therapy has been suggested as a treatment strategy for predominantly cystic nodules, as it is still unclear whether EA should be the first-line
Special Report Ha & Baek Table 1. Comparison of the treatment efficacy of ethanol ablation and radiofrequency ablation for thyroid nodules according to the proportion of the solid component. Proportion of the solid component Cystic nodule (50%)
Volume reduction ratio (%) EA
85.0–98.5 64.0–73.2 38.0–47.0
90.0–92.0 85.0–89.0 84.0–87.0
EA: Ethanol ablation; RFA: Radiofrequency ablation. Data taken from [4,10,12,24,31–34,37].
treatment for predominantly cystic thyroid nodules with a solid component greater than 20%, this issue should be verified in future studies. Solid thyroid nodules Previous studies of solid thyroid nodules showed that the volume reduction of EA (38–51%) [10–12] is much less than that of RFA (84–87%) [4,37] . Several studies revealed a 70–71% volume reduction ratio after EA for solid nodules [13,14] , and which is superior to that seen in previous EA studies (70–71% vs 38–51%); however, the mean treatment session was much greater (5–7.4 vs 1–1.9) in these studies. An increased number of treatment sessions could increase the rate of complications and could also decrease the cost–effectiveness. As EA is an inappropriate treatment modality for solid thyroid nodules, thermal ablation techniques, such as laser-, radiofrequency-, microwave- and high-intensity-focused ultrasound have been used to treat solid thyroid nodules. Among the different techniques, RFA and LA are two most often used thermal ablation techniques. Regarding the devices, two types of electrodes have been used for thyroid RFA; these are straight internally cooled electrodes (monopolar type) [23,38] and multi-tined expandable electrodes [19,39] . The former one has been used in South Korea and the latter one has been employed in Italy. The effectiveness of bipolar electrode for thyroid RFA has been recently reported in ex vivo study results [40,41] . Internally cooled electrodes are designed as water is circulated during the ablation to cool the tissue next to the electrode tip and prevent tissue carbonization  . Multi-tined expandable electrodes are designed with four to nine expandable hooks to make a large ablation zone at a time [19,39] . For thyroid LA, most procedures are currently performed either with Nd:YAG laser medium operating at 1064 nm or with diode lasers (800–980 nm) operating in the range of 2–4 W [26,42–43] .
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We would also like to verify the efficacy of the two most often used thermal ablation techniques, RFA and LA, by comparing the thyroid nodule volume reduction following treatment. In this article, a solid thyroid nodule is defined as a nodule having a solid component greater than 50%. Before comparing the two treatment modalities, we should note that there are four factors related to nodule volume reduction following treatment. The volume reduction is related to the number of treatment sessions [35,37–38] , the proportion of the solid nodule component [4,37] , the size of the initial nodule  and follow-up period duration [37,39,43] . Therefore, we compared the study results of two thermal ablation techniques using studies based on the following principles: a prospective single treatment session study; similar nodule volume (approximately 10 ml); proportion of a solid component greater than 50%; and follow-up of more than 6 months. In terms of the mean volume reduction, RFA [38,44–45] seems to be superior for volume reduction to LA (70.2–79.7 vs 44–57%) [16,35,46–48] . When we compared the studies with follow-up of more than 3 years, RFA revealed a 90% volume reduction at 1 year and a 93.4% volume reduction seen at the last follow-up period of 49 months. LA showed a 42.7–50.6% mean volume reduction at 1 year and 47.8–51% at the last follow-up (36–67 months) (Table 2) . These results indicate that RFA seems to be superior to LA in terms of volume reduction. Complications The complication rate after nonsurgical treatment is low after all three procedures and generally minor in severity. In a large population multicenter study of 1459 patients for RFA, the overall complication rate was 3.3% and the major complication rate 1.4%  . There have been no reports of procedure-related death; however, several sequelae have been reported
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Advances in nonsurgical treatment of benign thyroid nodules
Table 2. Comparison of the long-term treatment efficacy of radiofrequency ablation and laser ablation for thyroid nodules. Characteristics of the study
Lim et al. (2013)  Dossing et al. (2011)  Valcavi et al. (2010) 
Patients (nodules); n Ablation methods Initial volume (mean); ml Solidity (%) Treatment sessions (mean); n Mean follow-up period (months) VRR at 1-year follow-up (%) VRR at last follow-up (%)
111 (126) RFA 9.8 >0 2.2 49 89.9 93.4
78 (78) LA 8.2 >90 1 67 42.7 51.0
122 (122) LA 23.1 >80 1 36 50.6 47.8
LA: Laser ablation; RFA: Radiofrequency ablation; VRR: Volume reduction ratio.
in 0.14% (two out of 1459) of patients  . Although pain at the ablation site is the most common complaint during the procedure, the degree of pain is tolerable in most patients and usually self-limited. The moving shot technique of thyroid RFA is related to the low complication rate, and this technique is effective in treatment of hypervascular nodules using the friction heat and thus minimizing the heat-sink effect [29,38] . Since there has been no large series study evaluating the complication rate for LA and EA from published articles, further studies are required in the future for comparisons. Conclusion This article demonstrates how to select the best treatment modality according to the proportion of the solid component of thyroid nodules. In cystic thyroid nodules, EA should be the firstline treatment. In predominantly cystic thyroid nodules, the step-by-step treatment strategy – that is, EA followed by RFA, has been suggested; however, the best treatment modality has not yet been determined. For solid nodules, RFA seems to be superior to LA. In the future,
direct comparison studies of EA and RFA for predominantly cystic thyroid nodules or a comparison of RFA and LA for solid thyroid nodules will be helpful in order to be able to select the most successful treatment modality. Future perspective Prospective studies investigating the better treatment modality between the EA and RFA for predominantly cystic thyroid nodules with a solid component greater than 20% should be performed in the future. Direct comparison studies of RFA and LA for solid thyroid nodules will be helpful to verify the most successful treatment modality. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
EXECUTIVE SUMMARY Cystic thyroid nodules ●●
Ethanol ablation (EA) should be used as the first-line treatment for cystic thyroid nodules, which has comparable therapeutic efficacy to, but is less expensive than laser ablation (LA) or radiofrequency ablation (RFA).
Predominantly cystic thyroid nodules ●●
Step-by-step treatment – that is, EA–RFA combination therapy, for predominantly cystic thyroid nodules is an effective and practical treatment strategy.
Solid thyroid nodules ●●
EA is an inappropriate treatment modality for solid thyroid nodules. Between the RFA and LA, RFA seems to have a superior efficacy than LA.
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Special Report Ha & Baek 11 Bennedbaek FN, Karstrup S, Hegedus L.
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