Ethanol Sclerotherapy for Benign Thyroid Cysts

Sonographically Guided Ethanol Sclerotherapy for Benign Thyroid Cysts: Results in 22 Patients,

Yong Soo Cho, Ho Kyu Lee, Il Min Ahn, Soo Mee Lim, Dae Hong Kim, Choong Gon Choi and  Dae Chul Suh,  AJR January 2000 vol. 174 no. 1 213-216

Abstract

OBJECTIVE. We evaluate the efficacy and safety of sonographically guided ethanol sclerotherapy for benign thyroid cysts.
SUBJECTS AND METHODS. We examined 22 patients with benign thyroid cysts (13 complex cysts and nine pure cysts) confirmed by fine-needle aspiration biopsy. Sonographically guided aspiration of the cystic fluid was followed by instillation of absolute ethanol (99.9%) into the cystic cavity: the injected volume of ethanol was 40-100% of the volume of fluid aspirated. The procedure was performed every 1 or 3 months for one or two sessions (mean, 1.2 sessions). Follow-up sonography was performed 1-10 months after the final session, and we observed patients after ethanol sclerotherapy for complications.
RESULTS. The initial volume of the cysts ranged from 3.5 to 42 ml. In 21 patients, the volume of the cyst decreased or the cyst was obliterated. The volume of the cyst was reduced by 50-99% in 13 patients and by 1-49% in six patients, and the cyst was obliterated in two patients. In one patient, the volume of the cyst increased. The volume of ethanol instilled was significantly correlated with the volume reduction rate of the cyst. There was a difference in the volume reduction rate between patients in whom 10 ml or more of initial volume was used and those in whom less than 10 ml of initial volume was used; that is, the volume reduction rate of the group with the initial cyst volume of more than 10 ml was higher than that of the other group. Important long-standing and severe complications were not observed.
CONCLUSION. Sonographically guided ethanol sclerotherapy is a safe and effective tool for the therapy of benign thyroid cysts.

Introduction

Thyroid nodule is common and is found by clinical palpation in 4-7% of the population and during autopsy in up to 30-50% of cases [1, 2]. Approximately 5-10% of the clinically palpable nodules have been shown to be thyroid carcinoma [3]. Complex cysts account for 31% of thyroid nodules found on sonography, of which pure thyroid cysts comprise less than 1% [4, 5]. Fine-needle aspiration biopsy for thyroid nodules is being commonly used for diagnosis and treatment of thyroid cysts. However, aspiration by syringe is not appropriate for treatment because the recurrence rate after aspiration is as high as 58% depending on the size of cysts [6, 7]. Therefore, in cases of recurrence, percutaneous instillation of tetracycline and injection of ethanol are used [8, 9, 10, 11].

Sonographically guided percutaneous ethanol injection was first used for treatment of renal cysts and has been reportedly used for the treatment of autonomous thyroid adenoma with an efficacy rate of approximately 80% [12, 13, 14, 15]. Several researchers have reported the efficacy and safety of ethanol sclerotherapy for thyroid cystic nodules [5, 8,16, 17]. Hence, we intended to determine the efficacy and safety of sonographically guided ethanol sclerotherapy (hereinafter referred to as “sclerotherapy”) for benign thyroid cysts.

Subjects and Methods

Patients who were examined at our hospital because of a thyroid mass and underwent fine-needle aspiration—with biopsy confirming the mass to be a benign nodule—and then sclerotherapy and follow-up sonography were included in our study. Our study group consisted of 18 women and four men (age range, 23-61 years; mean age, 40.7 years) with 13 complex cysts and nine pure cysts. A thyroid cyst was defined as a nodule with a cystic component of more than 60%.
Most patients (n = 19) were concerned about the cosmetic implications of the nodules, and a few patients complained of local discomfort (n = 1) and dysphagia (n = 1) and expressed fear about malignancy (n = 1).

For sonography, an HDI 3000 scanner (Advanced Technology Laboratories, Bothell, WA) was used with a 5-10-MHz linear probe. The volume of a cyst, except a complex cyst, was determined using the following formula: length × width × height × π/6. For a complex cyst, volume was calculated as the volume of the cystic component other than solid areas.

Under sonographic guidance, a 20- to 22-gauge needle was inserted to aspirate cystic fluid as completely as possible without local anesthesia and then ethanol was slowly (approximately 2-5 ml/min) instilled into the cavity to a volume of 40-100% of the volume of aspirated fluid. The injection of ethanol was stopped if ethanol leaked out of the nodule or the patient complained of pain.

Four patients underwent sclerotherapy twice and the remaining 18 patients underwent the procedure once. Follow-up sonography was performed 1-10 months (mean, 3.5 months) after the final session and the side effects of ethanol sclerotherapy were evaluated by recording the symptoms of patients. The effectiveness of sclerotherapy was compared between two groups: in one group, 10 ml or more of baseline volume was injected; in the other group, less than 10 ml. In addition, the correlation between the volume of ethanol injected and the effect of sclerotherapy was determined. The effect of the therapy was presented as the volume reduction rate (volume reduction rate [%] = volume decrease [initial volume — final volume after treatment] / initial volume × 100%), and each case was classified into one of the following four groups: completely ablated cysts, cysts with a 50-99% reduction in volume, cysts with a 0-49% reduction in volume, and cysts with an increase in volume.

Results

The initial volume of cysts before sclerotherapy ranged from 3.5 to 42 ml (mean, 13.0 ml), the volume of cysts after therapy ranged from 0 to 17.5 ml (mean, 4.7 ml), and the mean volume reduction rate was 64%. The cysts disappeared completely in two patients (9%) (Fig. 1A), (Fig. 1B); the volume of the cyst decreased by 50-99% in 13 patients (59%) (Fig. 2A), (Fig. 2B), decreased by 1-49% in six patients (27%), and increased in one patient (5%) (Table 1).

Fig. 1. —33 year-old woman with complex thyroid cyst. A, Sonogram obtained before ethanol sclerotherapy shows complex cyst in right lobe of thyroid gland. Volume = 6.7 ml. B, Sonogram obtained 4 months after ethanol sclerotherapy reveals that cystic component of complex cyst has been almost obliterated.

Fig. 2. —46-year-old woman with pure thyroid cyst. A, Sonogram obtained before ethanol sclerotherapy shows pure cyst in left lobe of thyroid gland. Volume = 26.1 ml. B, Sonogram obtained 2 months after ethanol sclerotherapy reveals that volume of cyst decreased by 98%. Volume = 0.5 ml.

TABLE 1 Results of Ethanol Sclerotherapy of Cystic Thyroid Lesions in 22 Patients

  

TABLE 2 Correlation Between Volume of Ethanol Injected and Effect of Sclerotherapy in 22 Patients

The correlation between the volume of ethanol instilled and the volume reduction rate of cysts was confirmed: the higher the volume of ethanol instilled, the higher the rate of the volume reduction (r = 0.77, p < 0.01; Pearson's correlation analysis) (Table 2)x. However, no significant difference in the rate of volume reduction for either pure or complex cyst was seen (p > 0.005; two sample t test).

There was a difference in volume reduction rate between two groups—those in whom 10 ml or more of initial volume was injected and those in whom less than 10 ml of initial volume was injected; that is, the rate of volume reduction was higher for the group with the initial cyst volume of more than 10 ml when compared with the other group (p < 0.005; two sample t test).

Side effects associated with sclerotherapy were reported in two patients, both of whom complained of local pain at the injection site caused by leakage of a small amount of ethanol into the subcutaneous tissue. Pain was transient in both patients, and no severe complications were seen.

Discussion

Most solitary thyroid cysts are derived from hyperplastic nodules and are believed to be caused by cystic change or hemorrhage in pre-existing nodules [17].
Thyroid cysts rarely accompany malignant neoplasia. These cysts present as thyroid carcinoma in an average of 5% of patients, a lower probability than that of solid nodules [8]. Pure cysts are associated with a lower probability of malignancy than mixed cysts [5]. Malignant thyroid cysts confirmed by fine-needle aspiration biopsy usually require surgical treatment. However, for benign thyroid cysts, percutaneous tetracycline instillation, ethanol sclerotherapy, or thyroid hormone suppression therapy can be performed. Among these treatments, percutaneous aspiration has shown a high recurrence rate of up to 58% depending on the size of the cyst. Hence, for the treatment of recurrent cases, methods such as thyroid hormone suppression therapy and sclerosant instillation (sodium tetradecyl sulfate, hydroxy-polya-ethoxy-dodecan, tetracycline, or ethanol) were performed [18, 19]. Thyroid hormone suppression therapy was found to have no effect, whereas tetracycline instillation has been shown to be relatively effective. However, in a prospective study, researchers reported that tetracycline did not offer any advantage over isotonic saline in the treatment of thyroid cysts [20].

Ethanol, which is distributed in tissue by a diffusion mechanism, induces cellular dehydration and protein denaturation, which is followed by coagulation necrosis and reactive fibrosis [21].

Yasuda et al. [17] reported that the volume of the cyst decreased by more than 50% with ethanol sclerotherapy in 73% of patients treated for recurrent thyroid cysts after fine-needle aspiration. In our study, 68% of the patients with cystic nodules showed a decrease in volume of 50% or greater. Monzani et al. [16] also reported in a study in which they performed ethanol sclerotherapy and 12-month follow-up that cysts had relapsed in six of 20 patients, five of whom had a recurrence by the first month of follow-up, implying that most recurrence would occur within 1 month after treatment.

According to the report of Yasuda et al. [17], although no correlation between the volume of ethanol instilled and the volume reduction rate was seen, the recurrence rate after ethanol sclerotherapy was lower in the patient group in which the volume of aspirated fluid was less than 10 ml than in the other group. The results of our study, however, differ from those of Yasuda et al. We found the rate of volume reduction was greater in the group in which the volume of aspirated fluid was 10 ml or more compared with that of the other group in which the aspirated volume was less than 10 ml; in addition, we found that the more ethanol instilled, the greater the volume reduction rate of cysts. The reason for this difference is thought to be related to the fact that we used larger volumes of ethanol for our procedures than did Yasuda et al.

Although in recent studies some investigators reporting the effects of ethanol sclerotherapy have chosen to instill ethanol by the volume of one tenth to one third of the aspirated volume, we injected a higher volume of ethanol (approximately 40-100% of the aspirated fluid). According to our findings, the volume reduction rate increased, and side effects were not increased with more ethanol instilled. Therefore, we recommend that more ethanol be instilled to get an improved ablation effect in treatment for thyroid cyst. However, the chemical components or the viscosity of fluid are thought to inhibit diffusion of ethanol and, therefore, decrease the ablation effect.

Although investigators have reported there is a differences in the effects of sclerotherapy for thyroid nodules other than thyroid cysts, the effects of sclerotherapy for thyroid nodules differ little from those for thyroid cysts.

The frequency of complications after ethanol sclerotherapy is lower in thyroid cysts than thyroid nodules [12, 13, 14, 15, 21]. Complications of ethanol sclerotherapy, such as local pain at the injection site, transient hyperthyroidism, transient hoarseness, hematoma, and dyspnea, have been reported by several investigators [22, 23, 24]. Local pain at the injection site, the most common complication reported by all the investigators, occurs as a result of the leakage of ethanol into the subcutaneous tissue. Transitory hyperthyroidism has been reported by Antonelli et al. [8] and Kobayashi et al. [24]. In our study only two patients (9%) experienced transient local pain due to the leakage of a small amount of alcohol. However, because a thyroid function test was not performed before and after the sclerotherapy, thyroid function could not be evaluated.

In our series, several points can be mentioned as limitations. First, follow-up sonography was not performed at a regular interval. Second, although the volume reduction rate was found to increase with an increasing amount of ethanol, we could not determine the effective amount of ethanol relative to the volume of a cyst or the amount of aspirated fluid. The relationship between the chemical components and the viscosity of cystic fluid and the ablation effect of ethanol will need to be investigated to increase efficacy of ethanol sclerotherapy. Sometimes it is difficult to aspirate cystic fluid because of its higher viscosity; when this occurs, repeated instillation of ethanol is recommended. In addition, as we mentioned earlier, because the characteristic of cystic fluid might affect the treatment positively, we think more detailed studies regarding this point are necessary.

In conclusion, sonographically guided ethanol sclerotherapy is a safe and effective treatment for benign thyroid cysts.

      © American Roentgen Ray Society

Ultrasonography-guided ethanol ablation of predominantly solid thyroid nodules

Objectives: The aim of this study was to evaluate the success rate in ultrasonography-guided ethanol ablation (EA) of benign, predominantly solid thyroid nodules and to assess the value of colour Doppler ultrasonography in prediction of its success.

Methods: From January 2008 to June 2009, 30 predominantly solid thyroid nodules in 27 patients were enrolled. Differences in the success rate of EA were assessed according to nodule vascularity, nodule size, ratio of cystic component, amount of injected ethanol, degree of intranodular echo-staining just after ethanol injection and the number of EA sessions.

Results: On follow-up ultrasonography after EA for treatment of thyroid nodules, 16 nodules showed an excellent response (90% or greater decrease in volume) and 2 nodules showed a good response (50–90% decrease in volume) on follow-up ultrasonography. However, 5 nodules showed an incomplete response (10–50% decrease in volume) and 7 nodules showed a poor response (10% or less decrease in volume). Statistical analysis revealed a significant association of nodule vascularity (p=0.002) and degree of intranodular echo-staining just after ethanol injection (p=0.003) with a successful outcome; however, no such association was observed with regard to nodule size, ratio of cystic component, amount of infused ethanol and the number of EA sessions. No serious complications were observed during or after EA.

Conclusion: The success rate of EA was 60%, and nodule vascularity and intranodular echo-staining on colour Doppler ultrasonography were useful in predicting the success rate of EA for benign, predominantly solid thyroid nodules.

Technique of ethanol ablation

Written informed consent was obtained from all patients prior to each EA. EA was performed on an out-patient basis by a radiologist according to the following method. The operator used an empty 10-ml plastic syringe attached to either a conventional 21- or 23-gauge needle (23 gauge for a purely solid nodule or a predominantly solid nodule with a smaller cystic component, and 21 gauge for a predominantly solid nodule with a larger cystic component). During the entire procedure, the operator manoeuvred the ultrasonography probe with his left hand and the syringe–needle unit with his right hand. The ultrasonography probe was adjusted for centring the target nodule on the ultrasonography monitor.

The needle was inserted rapidly almost perpendicular to the neck while the operator applied positive pressure to the syringe piston using the thumb of his right hand in order to prevent an influx of blood into the needle lumen. The method of ethanol instillation differed according to whether the nodule was purely solid or predominantly solid. In the case of a purely solid nodule, absolute ethanol (99.9%) injection was administered directly.

Adequate coverage of the target nodule, as indicated by its echogenicity (called intranodular echo-staining), was achieved by adjusting the injection of ethanol under ultrasonography guidance; the needle–syringe unit was then rapidly withdrawn and the procedure was completed. In cases where the predominantly solid nodule contained a cystic component, the cystic component was punctured and almost completely aspirated, and an appropriate amount of ethanol was instilled. After replacement of the needle into the solid component of the target nodule by adjustment of the needle position, an appropriate amount of ethanol, which was in proportion to nodule size and echo-staining of the solid portion of the nodule, was infused. A single-puncture technique was used with no local anaesthesia. In all cases the amount of injected ethanol did not exceed 10ml. Any patient experiencing a sensation of drunkenness after EA was not allowed to drive herself/himself home. Additional EA was performed 1–2 months after the initial EA when the outcome of EA was determined to be unsuccessful on follow-up ultrasonography. The amount of infused ethanol, degree of intranodular echo-staining just after ethanol injection and presence of pain or other complications during or after the procedure were recorded for each patient.

Ultrasonography follow-up

Nodule volume was calculated during the latest thyroid ultrasonography before EA and during the final follow-up thyroid ultrasonography after EA. The difference in nodule volume was used as a criterion for determination of the success or failure of EA for treatment of thyroid nodules.

The other factor was the absence of, or marked reduction in, nodule vascularity. The outcome of EA was classified as follows, according to the decrease in nodule volume and nodule vascularity: poor response ( <10% decrease in volume, regardless of nodule vascularity), incomplete response (10–50% decrease in volume, regardless of nodule vascularity), good response (50–90% decrease in volume and decreased vascularity) and excellent response (> 90% decrease in volume and scanty vascularity). On real-time colour Doppler ultrasonography, nodule vascularity on the same-day ultrasonography, just before ethanol injection, and that of the last follow-up ultrasonography after EA were compared. Also, nodule volume measured on the same-day ultrasonography just before ethanol injection and that of the last follow-up ultrasonography after EA were compared. Furthermore, the success rate of EA was compared across the nodule size, ratio of the cystic component, amount of infused ethanol, degree of intranodular echo-staining by injected ethanol and the number of sessions of EA. Intranodular echo-staining was roughly estimated on the basis of real-time ultrasonography just after EA and classified as follows: no staining (nearly complete washout of injected ethanol), poor staining ( <10% of the injected area), mild staining (10–50% of the injected area) and moderate staining ( > 50% of the injected area) (Figure 1).

Discussion

Owing to its ease of use, safety, low cost and effectiveness, EA is the first-choice tool for use in the treatment of benign cystic thyroid nodules [17–26].

However, the efficacy and results of EA for the treatment of solid or predominantly solid thyroid nodules have been variable according to studies (Table 1) [2–14]. RFA or laser ablation has recently become a safe modality for use as an appropriate alternative to clinical follow-up, radioiodine therapy, surgery and EAtreatment of benign solid thyroid nodules [27–30]. RFA has proven to be a feasible and effective tool for treatment of solid nodules; however, its disadvantage lies in the high cost when compared with EA. Baek et al [29] suggested that RFA for the treatment of benign, predominantly solid thyroid nodules is effective for the reduction of nodule volume and relief of nodule-related clinical problems; they demonstrated a high success rate (100%) and a high mean volume reduction rate (79.7%) during a 6-month period of ultrasonography follow-up. In the present study, the mean success rate (60%) and volume reduction rate (64.3%) of EA were lower than those reported by Baek et al [29].

In this study, a significant relationship was observed between nodule vascularity and the success rate of EA. EA of predominantly solid thyroid nodules with high vascularity on colour Doppler ultrasonography showed worse results than those with low vascularity. In addition, venous washout of injected ethanol was frequently observed during EA of solid thyroid nodules with high vascularity. We found that poor venous washout of injected ethanol during EA was closely related to good intranodular echo-staining and good results, whereas moderate venous washout was closely related to poor intranodular echo-staining and poor results. Consequently, intranodular echo-staining is closely related to the success rate of EA. It may be hypothesised that effective ethanol ablation is possible only when the ethanol stays within the thyroid nodule and there is no venous washout of the injected ethanol. A long stay of ethanol with little washout can have an effect on sclerotic mechanisms of ethanol, which include coagulative necrosis, small-vessel thrombosis and haemorrhagic infarction [31]. Therefore, EA may become the first-line treatment when a symptomatic solid thyroid nodule shows low- or isovascularity in colour Doppler ultrasonography.

Only one or two EA sessions were conducted for each nodule in this study. We restricted additional EA sessions in case of a significant appearance of venous washout of the injected ethanol during the procedure or poor intranodular echo-staining immediately after ethanol injection; therefore, no more than two EA sessions were conducted. Furthermore, depending on nodule vascularity, degree of intranodular echo-staining and an unsuccessful result on follow-up ultrasonography, an additional EA session or RFA can be decided upon; thus, three or more EA sessions can be avoided.

The fact that EA of large solid thyroid nodules is less successful than EA of small ones is generally accepted [5, 8, 9, 14, 24]; however, other studies have demonstrated safe and effective techniques for treatment of large (.30ml) hyperfunctioning nodules [12]. Some investigators have emphasised that a higher dose of ethanol per session is more important than nodule size and could be significantly related to EA success [12]. However, we believe that intranodular echo-staining of the injected ethanol with no washout is more important than nodule size or the amount of ethanol injected per session.

Kim et al [13] insisted that the volume of instilled ethanol showed significant correlation with the volume reduction rate of cysts, but not that of solid nodules. The percentage of cystic components in the thyroid nodule has been shown to be closely associated with successful EA [14]. However, in the present study, nodules with a higher percentage of cystic components did not show good results in comparison with nodules with a lower percentage of cystic components. If the procedure were applied to predominantly solid thyroid nodules with low vascularity and high echo-staining without venous washout, we could expect a higher success rate before and during EA. Using this guideline for the selection of thyroid nodules, we could improve the therapeutic results of benign predominant thyroid nodules by choosing the most efficient therapeutic modality.

Ablation mechanisms of ethanol include coagulative necrosis and small-vessel thrombosis with haemorrhagic infarction [31]. An ablated portion of the nodule is replaced by a granulation tissue, followed by progressive shrinkage. Except for transient neck pain and discomfort, there was no occurrence of serious complications of EA in our study. We think that the most serious complication is necrosis of the adjacent normal soft and nerve tissue by leakage of injected ethanol [11, 15, 32]. To avoid complications, substantial experience and a precise ultrasound-guided injection are required. For reduction of side effects, the amount of ethanol injected during each session did not exceed 10 ml in our study. There is no definite guideline for an adequate amount of ethanol injected; in other studies, the maximum amount of ethanol injected per session varied from 7 to 14ml without serious complication [9, 11, 12].

There were several limitations to our study. First, the sample size was small and the range of nodule sizes or configurations broad. Therefore, large-scale studies are recommended in the future. Second, objective quantification of nodule vascularity, intranodular echo-staining and venous washout of injected ethanol was not performed. These were estimated and  subsequently classified by the ultrasonography operator. Finally, a thyroid scan was not performed before EA.

In summary, the success rate of EA was 60%, and EA of predominantly solid nodules was more effective in less vascular and more echo-staining thyroid nodules than in more vascular and less echo-staining ones.

Therefore, colour Doppler ultrasonography may be an useful tool for the prediction of treatment outcomes for EA of benign, predominantly solid thyroid nodules.