Cystic versus predominantly cystic thyroid nodules: efficacy of ethanol ablation and analysis of related factors
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To compare the efficacy of ethanol ablation (EA) of cystic and predominantly cystic thyroid nodules, and to evaluate factors affecting efficacy.
From October 2008 to December 2010, a total of 217 thyroid nodules were treated with EA. Nodule volumes, symptoms and cosmetic scores were evaluated before and after EA. EA efficacy in treating cystic and predominantly cystic nodules was compared; and factors related to EA efficacy in each type, including initial volume, solid component, vascularity, fluid nature, ethanol retention time and number of EA sessions, were evaluated.
Mean nodule volume decreased from 15.7 ± 18.1 ml to 3.0 ± 7.9 ml (mean volume reduction, 85.2 ± 16.1%) and the therapeutic success rate was 90.3% at last follow-up. EA was significantly more effective in cystic than predominantly cystic nodules. Independent predictors of EA efficacy for all nodules included initial volume, solid component and vascularity. Initial volume and vascularity were independent predictors of EA efficacy in predominantly cystic nodules, but no factor was independently related to efficacy in cystic nodules.
EA is effective in both cystic and predominantly cystic nodules, especially the former. EA is less effective in large or vascular predominantly cystic nodules, but is effective in cystic nodules regardless of related factors.
• Ethanol ablation under ultrasound guidance is increasingly used for cystic thyroid nodules.
• EA seems effective for cystic and predominantly cystic nodules, especially cystic nodules.
• The effectiveness of EA was reduced in large or vascular predominantly cystic nodules.
KeywordsEthanol ablation Radiofrequency ablation Thyroid cyst Thyroid nodule Thyroid intervention
Benign thyroid nodules are not uncommon, with ultrasound examination showing that 15–25% of solitary thyroid nodules are cystic or predominantly cystic [1, 2, 3]. Simple aspiration of the cystic portion is the initial treatment of choice, both for diagnosis and for reducing cyst volume. Collapse of thyroid cysts after simple aspiration have been reported; however, recurrence rates are as high as 80%, depending on the initial volume and internal contents of the nodule, and the number of aspirations [1, 4, 5, 6, 7]. For recurrent cases after aspiration, ethanol ablation (EA) has been attempted and achieved good results [2, 8, 9, 10].
Despite the effectiveness of EA in treating cystic and predominantly cystic thyroid nodules, about 5–25% of patients have nodules refractory to EA [1, 2, 8, 11]. The efficacy of repeat EA of refractory nodules is considerably reduced  and may be dependent on the percentage of solid component, the initial volume of the nodule and the amount of injected ethanol [2, 6, 7, 12]. The percentage of solid component has been shown to be the most important factor [13, 14]. Volume reduction after EA has been reported to be greater for cystic than for solid nodules (64% versus 35%), suggesting that solid components are more resistant to the diffusion of ethanol and that the vascularity of the solid component favours the drainage of ethanol, thus limiting the success of the procedure . Despite these findings, no study to date has evaluated the importance of the solid component by comparing the effects of EA on cystic and predominantly cystic thyroid nodules. We therefore tested the hypothesis that the efficacy of EA in cystic thyroid nodules is dependent on the percentage of solid component. To test this hypothesis, we retrospectively evaluated the efficacy of EA in a large series of cystic and predominantly cystic thyroid nodules. We also evaluated various factors related to the efficacy of EA.
Materials and methods
The protocol of this retrospective study was approved by our Institutional Review Board, which did not require patient approval or informed consent for review of images and medical records. However, all patients undergoing ultrasound-guided fine-needle aspiration (FNA) and EA provided written informed consent before each procedure.
Nodules with a cystic portion greater than 50%
Pressure symptoms or cosmetic problems
Serum thyroid hormone and thyrotropin concentrations within normal limits
Cytologically confirmed benign nodules after two separate ultrasound-guided FNAs
All patients underwent ultrasound and ultrasound-guided FNA examinations, performed by one of three radiologists (J.H.B., J.H.L. and J.Y.S.) all with 11–13 years experience in these techniques, using a 5- to 14-MHz linear probe fitted to a real-time ultrasound system (EUB-7500, Hitachi; iU-22, Philips; Aplio SSA-770A, Toshiba). Nodule size, proportion of solid component, vascularity and internal fluid composition were assessed on ultrasound and ultrasound-guided FNA. The three orthogonal diameters of each nodule (the largest diameter and two diameters perpendicular to it) were measured, and the volume of each nodule was calculated as: V = πabc/6 (where V is volume, a is the largest diameter, and b and c are the other two perpendicular diameters) [18, 19]. Nodules with <10% solid component were classified as cystic, whereas those with 10–50% solid component were classified as predominantly cystic. Vascularity was graded into four categories (grade 0, no intranodular vascularity; grade 1, perinodular vascularity only; grade 2, intranodular vascularity <50%; grade 3, intranodular vascularity >50%). Internal fluid composition was classified as colloid or non-colloid.
At enrolment, patients were asked to rate their symptom score on a 10-cm visual analogue scale (0–10). Physicians recorded a cosmetic grade (1, no palpable mass; 2, a palpable mass but no cosmetic problem; 3, cosmetic problem on swallowing only; 4, readily detected cosmetic problem) [20, 21, 22, 23].
All procedures were performed on an outpatient basis. None of the patients received intravenous sedatives or analgesics before or during the procedure. Patients were placed in a supine position with mild neck extension. After skin sterilisation and anaesthesia with 2% lidocaine at the puncture site, a 14– to 18-gauge needle was inserted into the nodule under ultrasound guidance via the trans-isthmic approach, thus preventing a change in the position of the needle tip and of ethanol leakage while swallowing [13, 14, 17, 18, 21, 22, 23, 24, 25]. The maximum volume of internal fluid was aspirated, residual debris or colloid was removed by saline irrigation , and 99% ethanol was injected slowly into the cystic space. The volume of injected ethanol usually corresponded to about 50% of the volume of aspirated fluid. Ethanol retention times for EAs performed by J.H.B., J.H.L. and J.Y.S. were 2, 5 and 10 min, respectively, the times used by each radiologist in clinical practice. The ethanol was removed completely, and the needle was withdrawn slowly with minimal negative pressure of the syringe, thus preventing ethanol leakage outside the thyroid gland. During and immediately after EA, any discomfort or complications associated with the procedure were evaluated. Procedure-related pain was graded into four categories (grade 0, no pain or mild pain similar to pain during lidocaine injection; grade 1, pain greater than lidocaine injection, but not needing medication; grade 2, pain needing medication; grade 3, EA procedure incompletely terminated due to severe pain). Patients stayed in the hospital for 30 min after the procedure.
Repeat EA or radiofrequency (RF) ablation was performed on patients with (1) incompletely resolved symptoms (symptom score reduction <50%) or cosmetic problems, and/or (2) nodules showing a residual solid portion with internal vascularity on follow-up ultrasound examination [13, 14, 18]. Before retreatment of each patient, we explained the advantages and disadvantages of repeat EA or RFA, based on previous results [13, 14, 22], allowing all patients to choose a preferred treatment.
Follow-up ultrasound and clinical examinations were identical to those performed before EA. Ultrasound examinations were performed 1, 3, 6 and 12 months or later after the initial procedure. We carefully evaluated the position and nature of the treated nodule. Post-EA nodules tend to show marked hypoechogenicity with reduction in volume . Thus, we could confirm that the nodule had undergone EA. Any complications during follow-up were evaluated.
All statistical analyses were performed using SPSS for Windows (version 18.0; SPSS, Chicago, IL, USA). Paired t-tests were used to compare changes in nodule volume, symptom score and cosmetic score from before EA to 1 month and last follow-up after EA. Student’s t-tests were used to compare volume reduction rate (VRR), and Pearson’s chi-squared test was used to compare rates of therapeutic success (volume reduction >50%) and need for additional treatment, of cystic and predominantly cystic thyroid nodules.
The relationships between VRR at last follow-up and various factors (initial volume, proportion of solid component, vascularity, internal fluid nature, ethanol retention time and number of sessions) were evaluated by bivariate correlation analysis. Multiple linear regression analysis was used to determine independent predictors of VRR, including initial volume (<10 ml versus >10 ml), proportion of solid component (cystic versus predominantly cystic), vascularity (grade 0 versus grades 1–3), nature of internal fluid (colloid versus non-colloid), ethanol retention time (<10 min versus 10 min), and number of sessions. One-way ANOVA was used to compare VRRs according to ethanol retention time (2 min versus 5 min versus 10 min). The significance level for all tests was defined as P < 0.05.
We performed ethanol ablation in 217 thyroid nodules (127 cystic and 90 predominantly cystic nodules). The mean volume was 15.7 ± 18.1 ml. The vascularity of the nodules was: grade 0, 88 nodules; grade 1, 119 nodules; grade 2, nine nodules; grade 3, one nodule. Internal contents were colloid in 36 nodules and non-colloid in 181. Twenty-nine nodules required additional treatment, including 15 that underwent repeat EA (two sessions each for 14 nodules and three sessions for 1 nodule) and 14 that were treated by RF ablation. The mean follow-up period was 6.0 ± 5.6 months (range, 1–25 months).
Efficacy of ethanol ablation in total thyroid nodules and subgroups
Total (n = 217)
15.7 ± 18.1
3.0 ± 7.9
2.9 ± 2.6
0.6 ± 1.0
3.7 ± 0.6
1.7 ± 0.9
Therapeutic success (%)
Cystic (n = 127)
14.8 ± 16.4
1.8 ± 4.6
2.6 ± 2.6
0.5 ± 1.0
3.7 ± 0.6
1.5 ± 0.7
Therapeutic success (%)
Predominantly cystic (n = 90)
16.6 ± 20.1
4.7 ± 10.9
3.3 ± 2.4
1.0 ± 1.3
3.8 ± 0.6
2.0 ± 1.0
Therapeutic success (%)
Subgroup analysis showed that, although the mean initial volume of cystic and predominantly cystic nodules did not differ significantly (14.8 ± 16.4 ml versus 16.6 ± 20.1 ml, P = 0.348), the mean VRR at last follow-up was significantly greater for cystic than for predominantly cystic nodules (89.7% versus 78.2%, P < 0.001). Therapeutic success rates were 96.1% in cystic and 82.2% in predominantly cystic nodules (P = 0.001). Additional treatment was required for 6 cystic (4.7%) and 23 predominantly cystic nodules (25.6%; P < 0.001)
Multivariate analysis of factors independently related to the efficacy of ethanol ablation in total thyroid nodules
Total thyroid nodules
β ± SE
−5.952 ± 2.172
Proportion of solid component
−9.206 ± 2.364
−7.006 ± 1.938
Internal fluid nature
−1.386 ± 2.786
−0.894 ± 0.519
Number of sessions
−4.302 ± 3.742
Multivariate analysis of factors independently related to the efficacy of ethanol ablation in subgroups
Predominatly cystic nodules
β ± SE
β ± SE
−10.384 ± 3.969
−1.734 ± 2.397
−11.608 ± 3.482
−3.262 ± 2.182
Internal fluid nature
3.543 ± 5.082
−3.333 ± 3.104
−0.922 ± 0.927
−0.523 ± 0.592
Number of sessions
−8.617 ± 5.312
−0.483 ± 6.562
Comparison of the efficacy according to the ethanol retention time
2 min (n = 41)
5 min (n = 69)
10 min (n = 107)
Initial volume (ml)
19.0 ± 19.1
18.2 ± 17.0
12.5 ± 17.9
Last volume (ml)
3.3 ± 4.0
3.5 ± 7.2
2.5 ± 9.4
Volume reduction (%)
83.2 ± 13.4
83.5 ± 19.3
86.5 ± 15.5
There were no complications during the procedure and follow-up periods, except for five patients who complained of grade 1 pain during and immediately after the procedure, but their pain was relieved within several minutes. There were no major complications after EA, such as voice change, infection, Horner’s syndrome, or permanent hyperthyroidism or hypothyroidism.
We have shown here that, although EA is effective and safe for both cystic and predominantly cystic nodules, it was more effective for cystic nodules than predominantly cystic nodules in terms of volume reduction, therapeutic success and additional treatment. Initial nodule volume and vascularity were independently associated with the efficacy of EA in predominantly cystic nodules, whereas no factors were related to EA efficacy in cystic nodules. We also found that an ethanol retention time of 2 min was sufficient.
Previous studies have reported that the efficacy of EA was 85–98.5% in cystic nodules [8, 9, 10, 27, 28], 64–73.2% in predominantly cystic nodules [6, 7, 29], and 38–47% in solid nodules [7, 30, 31, 32], with a recent study showing that EA was less effective in nodules with >20% solid component . Using a large series of 217 thyroid nodules in 209 patients, we also found that the percentage of solid component was an independent predictor of EA efficacy. We therefore divided these thyroid nodules into two groups, cystic and predominantly cystic, according to the proportion of solid component, and analysed factors associated with EA efficacy in each group separately.
We found that EA was significantly less effective for predominantly cystic nodules of an initial volume >10 ml and vascularity grades 1–3. Studies of the relationship between initial nodule volume and EA efficacy have yielded conflicting results, showing a negative correlation , no correlation or a positive correlation [2, 29]. As the percentage of solid component may increase in proportion to initial nodule volume, the efficacy of EA may be influenced by the initial volume of predominantly cystic nodules. In addition, drainage of ethanol during EA may be enhanced by internal vascularity, thus limiting the efficacy of EA .
We failed to identify any factors related to the efficacy of EA in cystic nodules, suggesting that EA is almost always effective in the treatment of cystic nodules, regardless of treatment or pre-treatment factors. These findings provide further evidence of the use of EA as a first-line treatment technique for cystic thyroid nodules [13, 14].
In most previous studies, injected ethanol was not removed, although other studies utilised ethanol retention times of 2 min [1, 32], 5 min  or 10 min [21, 22]. To our knowledge, our study is the first to show that EA efficacy is independent of ethanol retention time, indicating that retention for 2 min is sufficient. Ethanol reacts rapidly with cells, inducing cell death by lysing the cell membrane and denaturing proteins, resulting in vascular occlusion . As longer ethanol retention times may increase patient inconvenience and complications, a shorter retention time may be sufficient.
Only five of our 209 patients (2.4%) experienced mild local pain at the injection site, with all experiencing relief of pain after several minutes without medication. We found that injecting and aspirating the ethanol by one needle puncture through a trans-isthmic approach minimised complications. The trans-isthmic approach, by which the needle approaches from the medial (isthmus) to the lateral aspect of a targeted nodule, allows the needle to pass through sufficient thyroid parenchyma to prevent a change in the position of the needle tip during swallowing or talking, as well as preventing ethanol leakage outside the thyroid gland. This approach has been used for EA as well as for RF ablation of thyroid nodules [13, 14, 18, 20, 21, 22, 24].
In conclusion, we found that EA was effective for both cystic and predominantly cystic nodules, especially for the former. Although the effectiveness of EA was reduced in large (initial volume >10 ml) or vascular predominantly cystic nodules, it was effective in cystic nodules regardless of treatment or pretreatment factors.
- 13.Jang SW, Baek JH, Kim JK et al (2011) How to manage the patients with unsatisfactory results after ethanol ablation for thyroid nodules: role of radiofrequency ablation. Eur J Radiol. doi:10.1016/j.ejrad.2011.02.039