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Department of Endocrinology, Odense University Hospital, DK-5000 Odense C, Denmark
Address all correspondence and requests for reprints to: Finn Noe Bennedbæk, M.D., Ph.D., Department of Endocrinology M, Kloevervaenget 6, Odense University Hospital, DK-5000 Odense C, Denmark. E-mail: finn.bennedbaek{at}ouh.fyns-amt.dk.
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Abstract |
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2 ml) were randomly assigned to either subtotal cyst aspiration, flushing with 99% ethanol, and subsequent complete fluid aspiration (n = 33), or to subtotal cyst aspiration, flushing with isotonic saline, and subsequent complete fluid aspiration (n = 33). In case of recurrence (defined as cyst volume >1 ml) at the monthly evaluations, the treatment was repeated but limited to a maximum of three treatments. Procedures were US-guided, and patients were followed for 6 months. Age, sex, number of previous aspirations, pretreatment cyst volume, and serum TSH did not differ in the two groups. Cure (defined as a cyst volume 
1 ml at the end of follow-up) was obtained in 27 of 33 [82%; confidence interval (CI), 65–93] patients treated with ethanol and in 16 of 33 (48%; CI, 31–66) patients treated with saline (P = 0.006). In the ethanol group, 21 of 33 (64%) patients were cured after one session only, compared with six of 33 (18%) in the saline group (P = 0.002). The number of previous aspirations (P = 0.005) and baseline cyst volume (P = 0.005) had influence on outcome, i.e. the chance of success decreased with the number of previous aspirations and with increasing cyst volume. Seven patients (21%) treated with ethanol had moderate to severe pain (median duration, 5 min; CI, 2–10), and one had transient dysphonia. Indirect laryngoscopy was performed before and after the last session and was normal in all patients. We concluded that treatment of recurrent thyroid cysts with ethanol is superior to simple aspiration and flushing with saline and devoid of serious side effects. Our study demonstrates that flushing with ethanol is a clinically significant nonsurgical alternative for thyroid cysts that recur despite repeat aspirations.
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Introduction |
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In the case of a benign lesion, simple aspiration is the treatment of choice, but the recurrence rate is 10–80%, depending on the number of aspirations and the cyst volume (10, 11). The fact that a number of benign cystic nodules resolve spontaneously, given sufficient time, makes therapy superfluous in some (12). This is supported by results of two recent surveys in which 95 and 85%, respectively, of members of the American Thyroid Association and the European Thyroid Association suggested a conservative, i.e. nonsurgical, strategy for the benign solitary cystic thyroid nodule (13, 14). Provided a benign cytology, indications for therapy are symptoms of compression or cosmetic complaints. There is no evidence of a clinically significant effect on recurrence rate of thyroid cysts using suppressive therapy with T4 (15) or sclerotherapy with tetracycline (16). Nine studies using ethanol instillation in thyroid cysts have been published (17, 18, 19, 20, 21, 22, 23, 24, 25). All report a high success rate, but only one placebo-controlled study with a short-term follow-up of 1 month in a few patients is available (20). The aim of the present study was to determine whether US-guided ethanol injection reduces the recurrence rate of benign thyroid cysts in a large-scale, double-blind, randomized placebo-controlled study.
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Subjects and Methods |
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Eligible subjects included patients who were 20–70 yr of age and had a benign solitary cold palpable thyroid nodule causing local discomfort and/or cosmetic complaints. Patients were referred by their primary care physicians. Inclusion criteria were: 1) [99mTc]pertechnetate scintigraphy demonstrating a solitary cold nodule; 2) US-demonstrated solitary or prominent [additional nodule(s) <1 cm detected on US but not on the scintiscan] anechoic cystic lesion with no or less than 10% solid component and cyst volume at least 2 ml; 3) recurrence of the cyst fluid more than 1 month after primary aspiration; 4) cytological samples, obtained by FNAB under sonographic guidance, of the cyst fluid, the cyst wall and, if present, a residual solid component, to rule out malignancy; 5) euthyroidism; 6) normal serum calcitonin; 7) no major concomitant disease; 8) no medication affecting thyroid function; 9) no history of previous head or neck irradiation; and 10) normal indirect laryngoscopy. All patients lived in an area (county of Funen, Denmark) with a borderline-deficient iodine supply (26). The protocol was approved by the ethics committee of the county of Funen (journal no. 94/211) and the National Board of Health (journal no. 53123101994). All patients provided signed informed consent before randomization.
Measurements
US-guided FNAB ruled out malignancy in all patients, and only results of cystic colloid goiter or colloid goiter were considered for inclusion. In the case of nondiagnostic smears, FNAB was repeated, and if this was still nondiagnostic the patient was referred for surgery. The US examinations were performed using a LOGIQ 500 US scanner (GE Medical Systems, Milwaukee, WI) with a 12-MHz linear transducer (type 739L) mounted with a needle steering device for precise US-guided punctures. The total thyroid volume (normal range, 9.6–27.6 ml) was calculated on the basis of an ultrasonic scanning procedure using a 5.5-MHz compound scanner (type 1846, Brüel and Kjær, Naerum, Denmark) (27). For each patient, US measurements were performed by the same operator with blinding toward previous measurements.
Blood tests included serum total T4 (normal range, 65–135 nmol/liter) determined by RIA (Diagnostic Products Corp., Los Angeles, CA), serum total T3 (normal range, 1.00–2.10 nmol/liter) determined by RIA (Johnson & Johnson, Clinical Diagnostics Ltd., Amersham, UK), serum calcitonin (normal range, 0–0.10 µg/liter) determined by RIA (MediLab, Copenhagen, Denmark), and serum TSH (normal range, 0.30–4.0 mU/liter) determined by DELFIA (Wallac Oy, Turku, Finland). Free T4 and T3 indices were calculated by multiplying serum T4 and T3 levels by the percentage T3 resin uptake. Serum antithyroid peroxidase antibodies (normal range < 200 U/ml) were determined by RIA DYNO test (Brahms Diagnostica, Berlin, Germany). Only patients with normal serum calcitonin, thyroid hormone, and TSH levels were considered for inclusion.
Study design and treatment
Random allocation was achieved using a random number generator on a computer. Patients were assigned to 1) subtotal cyst aspiration, instillation and flushing with 99% ethanol, and subsequent complete fluid aspiration (without removing the needle) after 2 min and under continuous US control; or 2) subtotal cyst aspiration, instillation and flushing with isotonic saline, and subsequent complete fluid aspiration (without removing the needle) after 2 min and under continuous US control. After subtotal aspiration of the cyst, the syringe was detached, the needle left in situ, and a different syringe and needle were used for aspiration from the bottle. The aim was an ethanol or saline dose of one fourth to one half of the aspirated cyst fluid volume.
All patients were evaluated before and after 1, 2, 3, and 6 months (calculated from the last treatment session in case of recurrence, and therefore a need of a second or third treatment). Measurements included serum thyroid hormones and TSH, as well as thyroid cyst volume and total thyroid volume assessed by US. In case of recurrence (US-determined cyst volume >1 ml), treatment was repeated at the 1-month evaluation, and patients were submitted to a maximum of three treatments. In case of a fourth recurrence, patients were offered hemithyroidectomy, and the 1-month evaluation after the third and last treatment represented the end-point for these patients. In case of success, data from the 6-month evaluation were used in the evaluation of the efficacy of the treatment.
At the last visit, patients were asked to rate their present pressure symptoms and cosmetic complaints as present or absent (dichotomous data).
The study was carried out with complete blinding of both investigators (F.N.B. and L.H.) and patients. The Pharmacy of Odense University Hospital (Centralapoteket OUH) was responsible for the production of absolute ethanol (800 mg/ml) and isotonic saline, for preparation of bottles labeled "project ethanol vs. saline," and for providing sealed code lists. A pharmacist independent of the investigators provided the investigators with 68 sealed boxes (labeled patient no. 1, 2, etc.). Each box contained three sealed bottles with 10 ml of sterile fluid (34 x 3 with saline and 34 x 3 with ethanol), and each was labeled "project medicine." The corresponding list with codes detailing the content of the bottles was stored in a sealed envelope at the pharmacy. Complete blinding was maintained throughout the whole study period, and the sealed envelope with treatment codes was not broken until the 6-month evaluation of the last patient. Allocation of treatment was thus carried out in an unbiased way.
Sample size and statistical analysis
Given a type I error of 0.05 (two-sided), a power of 90%, and an a priori estimated clinically relevant difference of 40% gives a sample size of 34 patients in each group. The size of each group was thus predetermined.
Baseline variables were compared in the two treatment groups. Frequencies are listed for dichotomous variables, and median (and quartiles) are listed for ordered categorical and continuous variables. To evaluate the differences, we used the standard 
2 test for dichotomous variables, and for ordered categorical and continuous variables we used the Wilcoxon rank sum test.
The difference between the two treatment groups was evaluated by an odds ratio with confidence intervals and associated with a P value obtained from logistic regression. To evaluate whether the findings were stable against the possible influence of other variables, we performed a multiple logistic regression with listing of odds ratios, confidence intervals, and P values.
Two of the 68 patients were excluded due to technical difficulties in one and due to pain during the instillation procedure and therefore discontinuation of the treatment in the other. Not until the end of the study when the sealed code was broken was it established that one of the two excluded patients had been treated with saline and the other with ethanol.
The computer programs used were STATA statistical software (Stata Corporation, College Station, TX), release 7.0, 2001, and SPSS 11.5 (SPSS Inc., Chicago, IL).
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Results |
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Clinical data for the 66 consecutive patients are given in Table 1
. All patients were treated 4–12 wk after the last recurrence. The groups were similar regarding sex, age, nodule duration, and the number of recurrences after previous aspirations. Likewise, there were no statistical differences regarding the number of pure cysts, cysts with a minor solid component, and the presence of additional small nodules or volume estimates in the two treatment groups. Serum TSH values were similar; serum free T4 and free T3 indices were slightly lower in the saline group, but we consider this finding of no clinical significance.
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and 3)The median treatment volume given was 3.5 ml [quartiles, 2;5] in the percutaneous ethanol injection (PEI) group compared with 3.0 ml [2;5] in the saline (NaCl) group corresponding to 36% of the cyst volume in each group (P = 0.4). Treatment response differs markedly based on the median number of treatments given: 1 [1;2] in the PEI group compared with 3 [2;3] in the saline group (P = 0.0002). A total of 27 patients (82%) treated with PEI were cured, 21 of whom (78%) were cured after only one treatment, compared with a total of 16 patients (48%) treated with saline, six of whom (38%) were cured after one treatment—a highly significant difference between the two treatment groups (P = 0.006). Failure, on the other hand, was seen in six (18%) in the PEI group compared with 17 (52%) in the saline group. A priori failure was defined as a cyst volume of more than 1 ml, and this was chosen on clinical grounds as a volume reduction from e.g. 20 to 8 ml; this may represent a statistically significant change but not necessarily a clinically relevant change that is satisfactory for the patient. The median reduction in cyst volume was 100% [83;100] in the PEI group, compared with 68% [21;94] in the saline group (P = 0.001). Results from the 3- and 6-month evaluations did not differ.
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, the number of previous aspirations influences the success rate, i.e. the higher the number of previous aspirations, the smaller the chance of treatment success (P = 0.005). Gender does not influence outcome, but there is a nonsignificant trend toward female sex being advantageous. Likewise, there is a trend toward nodule duration and also the presence of additional nodules influencing the chance of success. Pretreatment cyst volume, however, does influence the chance of success, i.e. having smaller cysts being advantageous (P = 0.005), whereas total thyroid volume has only a borderline-significant effect on outcome (P = 0.05). Age and US findings (cystic vs. complex) do not influence outcome. The presence or absence of pressure symptoms and/or cosmetic complaints at the end of follow-up correlated in all but one of the 66 patients to the a priori chosen cut-off limit of a cyst volume larger or smaller than 1 ml.
Side effects
Seven patients (21%) in the ethanol group reported transient pain/tenderness, with a duration of 10 min or less in six patients and 1 h in one patient. Only one patient in the saline group reported pain lasting for 10 min after treatment. One patient in the PEI group had transient dysphonia lasting for 1 h, but all patients, including the latter, had a normal indirect laryngoscopy after treatment. Due to treatment failure, a hemithyroidectomy was subsequently performed in all six patients treated with PEI; in one of these patients, the surgeon described periglandular fibrosis making the surgical procedure more difficult but causing no complications. No further side effects were encountered, and thyroid function remained unaltered throughout the entire period of follow-up (data not given). Among the saline treatment failures (n = 17), all were offered surgery according to the protocol, but seven refused surgery and were offered follow-up with repeat aspiration or treatment with PEI. Ten patients were thus referred for surgery (hemithyroidectomy). The procedure was uncomplicated in all except for postoperative bleeding in one patient necessitating reoperation, but no periglandular fibrosis was described.
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Discussion |
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In benign nodular thyroid disease, PEI has been introduced as an alternative to surgery (cold or hot nodules) or radioiodine therapy (hot nodules) (29). In benign cystic thyroid nodules this technique was introduced in 1989, and published studies comprise 345 patients with a cystic thyroid nodule treated with PEI (Table 4). The success rate, defined as near disappearance or marked (>50%) size reduction, varies from 72 to 95%. In the only placebo-controlled study with only one treatment, the short-term (1 month) success rate in 10 patients was 80% in the group treated with ethanol and 30% in the group treated with simple aspiration (20). Long-term follow-up (12 months) in 32 consecutive patients treated once with ethanol confirms the preliminary results obtained in the smaller randomized study (20). The remaining studies lack an evaluation of success rate based on number of ethanol instillations and an adequate control group. In an open study with a control group, 26 patients treated with one to five ethanol instillations had a 77% success rate, but the control group treated with saline underwent only one treatment, hampering the evaluation owing to the fact that repeated treatments with saline will also increase the cure rate (21). In larger and symptomatic thyroid cysts, the treatment also seems effective as shown in a study comprising 43 selected patients with a mean volume of 38 ml showing a success rate (near disappearance or >50% reduction) of 93% after 2 yr (23). In a recent large-scale study of 98 patients, one third of the cysts were larger than 40 ml, and only six patients with an initial response to PEI relapsed during a mean follow-up of 10 yr (25). Transient pain was reported by 71% of patients and dysphonia lasting for 1 yr in one patient, but no further side effects were reported in this study (25).
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The technique used by us is flushing with absolute ethanol (
99%) in an amount of 25–50% of the cyst volume (maximum 10 ml), preceded by a submaximal aspiration (90%) of the cyst fluid under US guidance. Ethanol is left in place for 2 min, and subsequently a complete aspiration is performed. As opposed to the technique described in the published studies on PEI in thyroid cysts, we recommend subsequent complete aspiration of ethanol. It is important to recognize that each ethanol injection carries a risk of ethanol escaping outside the capsule, inducing paraglandular fibrosis as described in patients with solid cold thyroid nodules treated with PEI (30). This was seen in one of six patients with relapse in the PEI group subjected to subsequent hemithyroidectomy and in none in the saline group. However, side effects of ethanol instillation into cystic thyroid nodules seem to be few and are generally described as mild and transient, except for one case of respiratory distress and emergency surgical treatment (31). In our experience, pain is less pronounced and of shorter duration than that described after injections into solid structures, and transient pain (duration of 10 min or less in six of seven patients) was only seen in 21% of patients treated with ethanol in the present study. Based on these findings, it seems that there is no need for local anesthesia. This is supported by the study by Zingrillo et al. (23) reporting a mild transient pain/"burning sensation" radiating to the ear or neck in 12% of the treatment sessions, although a higher rate (71%) was observed in patients treated with larger thyroid cysts (25). Among the saline treatment failures referred for surgery, one patient needed reoperation due to bleeding, but no further complications were encountered in this group. Histology confirmed the pretreatment cytological diagnosis in all but one patient, in whom a diagnosis of a benign follicular adenoma was made.
Our study demonstrates that US-guided PEI with subsequent complete aspiration is feasible, safe, and superior to flushing with isotonic saline. The technique is rapid and can be performed on an outpatient basis. It is a clinically significant alternative to surgery in recurrent thyroid cysts, provided diagnostic biopsy results exclude malignancy.
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Acknowledgments |
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Footnotes |
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The results of this study were presented in part at the 85th Annual Meeting of The Endocrine Society, Philadelphia, PA, 2003.
Abbreviations: FNAB, Fine-needle aspiration biopsy; PEI, percutaneous ethanol injection; US, ultrasonography.
Received June 10, 2003.
Accepted August 21, 2003.
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