J. Clin. Endocrinol. Metab. 2003 88: 5773-5777, doi: 10.1210/jc.2003-031000  

Finn Noe Bennedbæk and Laszlo Hegedüs  

Controlled TrialTreatment of Recurrent Thyroid Cysts with Ethanol: A Randomized Double-Blind

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Treatment of Recurrent Thyroid Cysts with Ethanol:A Randomized Double-Blind Controlled Trial

FINN NOE BENNEDBÆK AND LASZLO HEGEDUS

Department of Endocrinology, Odense University Hospital, DK-5000 Odense C, Denmark

Thyroid nodules are prevalent; when evaluated by ultra-sonography (US), 15–25% of solitary thyroid nodules are cysticor predominantly cystic, and most are benign. Simple aspi-ration is the treatment of choice, but the recurrence rate is10–80% depending on the number of aspirations and the cystvolume. The aim of this study was to evaluate the effect onrecurrence rate of benign recurrent thyroid cysts in a double-blind randomized study comparing ethanol instillation withinstillation of isotonic saline and subsequent complete emp-tying. Sixty-six consecutive patients with recurrent and be-nign (based on US-guided biopsy) thyroid cysts (>2 ml) wererandomly assigned to either subtotal cyst aspiration, flushingwith 99% ethanol, and subsequent complete fluid aspiration(n � 33), or to subtotal cyst aspiration, flushing with isotonicsaline, and subsequent complete fluid aspiration (n � 33). Incase of recurrence (defined as cyst volume >1 ml) at themonthly evaluations, the treatment was repeated but limitedto 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 obtainedin 27 of 33 [82%; confidence interval (CI), 65–93] patientstreated with ethanol and in 16 of 33 (48%; CI, 31–66) patientstreated with saline (P � 0.006). In the ethanol group, 21 of 33(64%) patients were cured after one session only, comparedwith six of 33 (18%) in the saline group (P � 0.002). The numberof previous aspirations (P � 0.005) and baseline cyst volume(P � 0.005) had influence on outcome, i.e. the chance of successdecreased with the number of previous aspirations and withincreasing cyst volume. Seven patients (21%) treated with eth-anol had moderate to severe pain (median duration, 5 min; CI,2–10), and one had transient dysphonia. Indirect laryngos-copy was performed before and after the last session and wasnormal in all patients.

We concluded that treatment of recurrent thyroid cystswith ethanol is superior to simple aspiration and flushingwith saline and devoid of serious side effects. Our study dem-onstrates that flushing with ethanol is a clinically significantnonsurgical alternative for thyroid cysts that recur despiterepeat aspirations. (J Clin Endocrinol Metab 88: 5773–5777,2003)

NODULAR THYROID DISEASE remains a commonclinical problem; when evaluated by ultrasonogra-

phy (US), 15–25% of solitary thyroid nodules are cystic orpredominantly cystic (1), and similarly, 18–37% of all sur-gically excised thyroid nodules are cystic (2–5). The demon-stration of the cystic nature of a thyroid nodule does not ruleout malignancy (3, 5, 6). Most endocrinologists agree thatreliance on fine-needle aspiration biopsy (FNAB) is essentialfor an optimal management strategy (1, 7, 8). To improve theresults of cytology, US-guided FNAB of the wall and solidportion of the cystic nodule along with cytology of the cysticfluid has been introduced and shown to improve the diag-nostic accuracy (9).

In the case of a benign lesion, simple aspiration is thetreatment of choice, but the recurrence rate is 10–80%, de-pending on the number of aspirations and the cyst volume(10, 11). The fact that a number of benign cystic nodulesresolve spontaneously, given sufficient time, makes therapysuperfluous in some (12). This is supported by results of tworecent surveys in which 95 and 85%, respectively, of mem-bers of the American Thyroid Association and the EuropeanThyroid Association suggested a conservative, i.e. nonsur-gical, strategy for the benign solitary cystic thyroid nodule(13, 14). Provided a benign cytology, indications for therapyare symptoms of compression or cosmetic complaints. There

is no evidence of a clinically significant effect on recurrencerate of thyroid cysts using suppressive therapy with T4 (15)or sclerotherapy with tetracycline (16). Nine studies usingethanol instillation in thyroid cysts have been published(17–25). All report a high success rate, but only one placebo-controlled study with a short-term follow-up of 1 month ina few patients is available (20). The aim of the present studywas to determine whether US-guided ethanol injection re-duces the recurrence rate of benign thyroid cysts in a large-scale, double-blind, randomized placebo-controlled study.

Subjects and MethodsSubjects

Eligible subjects included patients who were 20–70 yr of age and hada benign solitary cold palpable thyroid nodule causing local discomfortand/or cosmetic complaints. Patients were referred by their primarycare physicians. Inclusion criteria were: 1) [99mTc]pertechnetate scintig-raphy demonstrating a solitary cold nodule; 2) US-demonstrated solitaryor prominent [additional nodule(s) �1 cm detected on US but not on thescintiscan] anechoic cystic lesion with no or less than 10% solid com-ponent and cyst volume at least 2 ml; 3) recurrence of the cyst fluid morethan 1 month after primary aspiration; 4) cytological samples, obtainedby FNAB under sonographic guidance, of the cyst fluid, the cyst walland, if present, a residual solid component, to rule out malignancy; 5)euthyroidism; 6) normal serum calcitonin; 7) no major concomitantdisease; 8) no medication affecting thyroid function; 9) no history ofprevious head or neck irradiation; and 10) normal indirect laryngoscopy.All patients lived in an area (county of Funen, Denmark) with a bor-derline-deficient iodine supply (26). The protocol was approved by theethics committee of the county of Funen (journal no. 94/211) and the

Abbreviations: FNAB, Fine-needle aspiration biopsy; PEI, percuta-neous ethanol injection; US, ultrasonography.

0021-972X/03/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 88(12):5773–5777Printed in U.S.A. Copyright © 2003 by The Endocrine Society

doi: 10.1210/jc.2003-031000

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National Board of Health (journal no. 53123101994). All patients pro-vided signed informed consent before randomization.

Measurements

US-guided FNAB ruled out malignancy in all patients, and onlyresults of cystic colloid goiter or colloid goiter were considered forinclusion. In the case of nondiagnostic smears, FNAB was repeated, andif this was still nondiagnostic the patient was referred for surgery. TheUS examinations were performed using a LOGIQ 500 US scanner (GEMedical Systems, Milwaukee, WI) with a 12-MHz linear transducer(type 739L) mounted with a needle steering device for precise US-guidedpunctures. The total thyroid volume (normal range, 9.6–27.6 ml) wascalculated on the basis of an ultrasonic scanning procedure using a5.5-MHz compound scanner (type 1846, Bruel and Kjær, Naerum, Den-mark) (27). For each patient, US measurements were performed by thesame 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), se-rum total T3 (normal range, 1.00–2.10 nmol/liter) determined by RIA(Johnson & Johnson, Clinical Diagnostics Ltd., Amersham, UK), serumcalcitonin (normal range, 0–0.10 �g/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 andT3 indices were calculated by multiplying serum T4 and T3 levels by thepercentage 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 se-rum calcitonin, thyroid hormone, and TSH levels were considered forinclusion.

Study design and treatment

Random allocation was achieved using a random number generatoron a computer. Patients were assigned to 1) subtotal cyst aspiration,instillation and flushing with 99% ethanol, and subsequent completefluid aspiration (without removing the needle) after 2 min and undercontinuous US control; or 2) subtotal cyst aspiration, instillation andflushing with isotonic saline, and subsequent complete fluid aspiration(without removing the needle) after 2 min and under continuous UScontrol. After subtotal aspiration of the cyst, the syringe was detached,the needle left in situ, and a different syringe and needle were used foraspiration from the bottle. The aim was an ethanol or saline dose of onefourth 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, andtherefore a need of a second or third treatment). Measurements includedserum thyroid hormones and TSH, as well as thyroid cyst volume andtotal thyroid volume assessed by US. In case of recurrence (US-deter-mined cyst volume �1 ml), treatment was repeated at the 1-monthevaluation, and patients were submitted to a maximum of three treat-ments. In case of a fourth recurrence, patients were offered hemithy-roidectomy, and the 1-month evaluation after the third and last treat-ment represented the end-point for these patients. In case of success, datafrom the 6-month evaluation were used in the evaluation of the efficacyof the treatment.

At the last visit, patients were asked to rate their present pressuresymptoms and cosmetic complaints as present or absent (dichotomousdata).

The study was carried out with complete blinding of both investi-gators (F.N.B. and L.H.) and patients. The Pharmacy of Odense Uni-versity Hospital (Centralapoteket OUH) was responsible for the pro-duction of absolute ethanol (800 mg/ml) and isotonic saline, forpreparation of bottles labeled “project ethanol vs. saline,” and for pro-viding sealed code lists. A pharmacist independent of the investigatorsprovided 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 � 3 with saline and 34 � 3 with ethanol), and each was labeled“project medicine.” The corresponding list with codes detailing thecontent 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 thuscarried 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 prioriestimated clinically relevant difference of 40% gives a sample size of 34patients in each group. The size of each group was thus predetermined.

Baseline variables were compared in the two treatment groups. Fre-quencies are listed for dichotomous variables, and median (and quar-tiles) are listed for ordered categorical and continuous variables. Toevaluate the differences, we used the standard �2 test for dichotomousvariables, and for ordered categorical and continuous variables we usedthe Wilcoxon rank sum test.

The difference between the two treatment groups was evaluated byan odds ratio with confidence intervals and associated with a P valueobtained from logistic regression. To evaluate whether the findings werestable against the possible influence of other variables, we performed amultiple logistic regression with listing of odds ratios, confidence in-tervals, and P values.

Two of the 68 patients were excluded due to technical difficulties inone and due to pain during the instillation procedure and thereforediscontinuation of the treatment in the other. Not until the end of thestudy when the sealed code was broken was it established that one ofthe two excluded patients had been treated with saline and the otherwith ethanol.

The computer programs used were STATA statistical software (StataCorporation, College Station, TX), release 7.0, 2001, and SPSS 11.5 (SPSSInc., Chicago, IL).

ResultsPretreatment findings

Clinical data for the 66 consecutive patients are given inTable 1. All patients were treated 4–12 wk after the lastrecurrence. The groups were similar regarding sex, age, nod-ule duration, and the number of recurrences after previousaspirations. Likewise, there were no statistical differencesregarding the number of pure cysts, cysts with a minor solidcomponent, and the presence of additional small nodules orvolume estimates in the two treatment groups. Serum TSHvalues were similar; serum free T4 and free T3 indices wereslightly lower in the saline group, but we consider this find-ing of no clinical significance.

Treatment response (Tables 2 and 3)

The median treatment volume given was 3.5 ml [quartiles,2;5] in the percutaneous ethanol injection (PEI) group com-pared with 3.0 ml [2;5] in the saline (NaCl) group corre-sponding to 36% of the cyst volume in each group (P � 0.4).Treatment response differs markedly based on the mediannumber of treatments given: 1 [1;2] in the PEI group com-pared with 3 [2;3] in the saline group (P � 0.0002). A total of27 patients (82%) treated with PEI were cured, 21 of whom(78%) were cured after only one treatment, compared witha total of 16 patients (48%) treated with saline, six of whom(38%) were cured after one treatment—a highly significantdifference between the two treatment groups (P � 0.006).Failure, on the other hand, was seen in six (18%) in the PEIgroup compared with 17 (52%) in the saline group. A priorifailure was defined as a cyst volume of more than 1 ml, andthis was chosen on clinical grounds as a volume reductionfrom e.g. 20 to 8 ml; this may represent a statistically signif-icant change but not necessarily a clinically relevant changethat is satisfactory for the patient. The median reduction in

5774 J Clin Endocrinol Metab, December 2003, 88(12):5773–5777 Bennedbæk and Hegedus • Ethanol Sclerotherapy of Thyroid Cysts

cyst volume was 100% [83;100] in the PEI group, comparedwith 68% [21;94] in the saline group (P � 0.001). Results fromthe 3- and 6-month evaluations did not differ.

As seen in Table 3, the number of previous aspirationsinfluences the success rate, i.e. the higher the number ofprevious aspirations, the smaller the chance of treatmentsuccess (P � 0.005). Gender does not influence outcome, butthere is a nonsignificant trend toward female sex being ad-vantageous. Likewise, there is a trend toward nodule dura-tion and also the presence of additional nodules influencingthe chance of success. Pretreatment cyst volume, however,does influence the chance of success, i.e. having smaller cystsbeing advantageous (P � 0.005), whereas total thyroid vol-ume has only a borderline-significant effect on outcome (P �

0.05). Age and US findings (cystic vs. complex) do not in-fluence outcome.

The presence or absence of pressure symptoms and/orcosmetic complaints at the end of follow-up correlated in allbut one of the 66 patients to the a priori chosen cut-off limitof a cyst volume larger or smaller than 1 ml.

Side effects

Seven patients (21%) in the ethanol group reported tran-sient pain/tenderness, with a duration of 10 min or less in sixpatients and 1 h in one patient. Only one patient in the salinegroup reported pain lasting for 10 min after treatment. Onepatient in the PEI group had transient dysphonia lasting for

TABLE 1. Baseline characteristics in the two treatment groups

Variable PEI NaCl P

Sex (M/F) 4/29 7/26 0.3Age (yr) 48 [33;57] 46 [40;53] 0.9Previous surgery/131-I 2 4 0.3Months from diagnosis 9 [4;12] 7 [4;13] 0.8Previous number of aspirations 1 [1;2] 1 [1;2] 0.6US findings

Solitary cyst 26 26 1Solitary and predominantly cystic 7 7Solitary lesion 23 24 0.98Additional small nodules 10 9Cyst volume (ml) 8.0 [5;14] 8.0 [4;15] 0.8Thyroid volume (ml) 26 [20;35] 32 [18;42] 0.5Cyst fluid appearance

Clear/yellow 13 11 0.6Bloody/brownish 20 22

Biochemical measurementsTSH (mU/liter) (normal, 0.3–4) 0.95 [0.6;1.4] 0.95 [0.7;1.1] 0.85FT4-I (U/liter) (normal, 60–140) 102 [88;116] 88 [79;100] 0.02FT3-I (U/liter) (normal, 0.95–2.20) 1.7 [1.5;1.9] 1.5 [1.4;1.7] 0.02

Values are medians (with the 25th and 75th centiles-quartiles) or number of cases. FT4, Free T4; FT3, free T3.

TABLE 2. Treatment characteristics and response

PEI NaCl P

Treatment-volume (ml) 3.5 [2;5] 3.0 [2;5] 0.7% Treatment-volume 36 [25;48] 36 [27;50] 0.4No. of treatments 1 [1;2] 3 [2;3] 0.0002Cure after

1 treatment 21 62 treatments 4 7 0.0063 treatments 2 3Failure 6 17

% Cyst volume-reduction 100 [83;100] 68 [21;94] 0.001

Values are medians (with quartiles) or number of cases.

TABLE 3. Effect of variables on treatment response

VariableMultivariate effects on treatment success

Univariate OROR P CI

Ethanol vs. saline 27.752 0.005 2.699 285.357 4.781Previous aspirations 0.058 0.005 0.008 0.419 0.380Gender 2.435 0.524 0.157 37.740 0.373Age 1.026 0.561 0.940 1.121 0.969Months from diagnosis 1.039 0.179 0.983 1.098 0.987Cystic vs. complex 0.855 0.873 0.125 5.867 0.648Additional nodules 7.820 0.127 0.559 109.432 0.344Cyst volume 0.830 0.005 0.728 0.945 0.886Thyroid volume 0.921 0.052 0.847 1.001 0.951

OR, Odds ratio; CI, confidence interval.

Bennedbæk and Hegedus • Ethanol Sclerotherapy of Thyroid Cysts J Clin Endocrinol Metab, December 2003, 88(12):5773–5777 5775

1 h, but all patients, including the latter, had a normal indirectlaryngoscopy after treatment. Due to treatment failure, ahemithyroidectomy was subsequently performed in all sixpatients treated with PEI; in one of these patients, the sur-geon described periglandular fibrosis making the surgicalprocedure more difficult but causing no complications. Nofurther side effects were encountered, and thyroid functionremained unaltered throughout the entire period of fol-low-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 withrepeat aspiration or treatment with PEI. Ten patients werethus referred for surgery (hemithyroidectomy). The proce-dure was uncomplicated in all except for postoperativebleeding in one patient necessitating reoperation, but noperiglandular fibrosis was described.

Discussion

Fine-needle aspiration of cystic thyroid nodules is a com-mon cause of nondiagnostic rather than false-negative re-sults. Recommendations for treatment should be based oncytological results or failure of cyst resolution alone (2). Al-though aspiration may be of therapeutic value, the reportedefficacy varies considerably (28). The success rate largelydepends on the cyst volume and the number of previousaspirations.

In benign nodular thyroid disease, PEI has been intro-duced as an alternative to surgery (cold or hot nodules) orradioiodine therapy (hot nodules) (29). In benign cystic thy-roid nodules this technique was introduced in 1989, andpublished studies comprise 345 patients with a cystic thyroidnodule treated with PEI (Table 4). The success rate, definedas near disappearance or marked (�50%) size reduction,varies from 72 to 95%. In the only placebo-controlled studywith only one treatment, the short-term (1 month) successrate in 10 patients was 80% in the group treated with ethanoland 30% in the group treated with simple aspiration (20).Long-term follow-up (12 months) in 32 consecutive patientstreated once with ethanol confirms the preliminary resultsobtained in the smaller randomized study (20). The remain-ing studies lack an evaluation of success rate based on num-ber of ethanol instillations and an adequate control group. In

an open study with a control group, 26 patients treated withone to five ethanol instillations had a 77% success rate, butthe control group treated with saline underwent only onetreatment, hampering the evaluation owing to the fact thatrepeated treatments with saline will also increase the curerate (21). In larger and symptomatic thyroid cysts, the treat-ment also seems effective as shown in a study comprising 43selected patients with a mean volume of 38 ml showing asuccess rate (near disappearance or �50% reduction) of 93%after 2 yr (23). In a recent large-scale study of 98 patients, onethird of the cysts were larger than 40 ml, and only six patientswith an initial response to PEI relapsed during a mean fol-low-up of 10 yr (25). Transient pain was reported by 71% ofpatients and dysphonia lasting for 1 yr in one patient, but nofurther side effects were reported in this study (25).

Our study shows that PEI sclerotherapy reduces recur-rence rate of thyroid cysts relapsed after evacuation aloneand that cure was obtained in 64% of patients after onetreatment only and in 82% overall. This contrasts with the48% who were cured after simple aspiration and flushingwith saline, of whom only 18% were cured by one treatment.Although a definition of failure as a thyroid cyst volume of1 ml seems rigorous, it is based on clinical grounds. In mostpublished studies on PEI in thyroid cysts, a success rate isdefined as near disappearance or marked (�50%) size re-duction of the cystic lesion. In our experience, most cysticnodules vary in size, and although size reduction is oftenseen during follow-up of cysts primarily evacuated, theytend to increase gradually given enough time.

The technique used by us is flushing with absolute ethanol(�99%) in an amount of 25–50% of the cyst volume (maxi-mum 10 ml), preceded by a submaximal aspiration (�90%)of the cyst fluid under US guidance. Ethanol is left in placefor 2 min, and subsequently a complete aspiration is per-formed. As opposed to the technique described in the pub-lished studies on PEI in thyroid cysts, we recommend sub-sequent complete aspiration of ethanol. It is important torecognize that each ethanol injection carries a risk of ethanolescaping outside the capsule, inducing paraglandular fibro-sis as described in patients with solid cold thyroid nodulestreated with PEI (30). This was seen in one of six patients withrelapse in the PEI group subjected to subsequent hemithy-

TABLE 4. PEI in cystic thyroid nodules: listing of published studies

Author Yr ofpublication

No. of patientstreated

Follow-up(months) Study design No. of

treatmentsSuccess ratea

(%)

Rozman (17) 1989 13 8 Open 1 77Yasuda (18) 1992 61 6 Open 1–4 72Monzani (19) 1994 20 12 Open 1–2 95Verde (20) 1994 10 1 Randomized 1 80

10b 1 1 3032 12 Open 1 80

Antonelli (21) 1994 26 12 Open 1–5 7744c 12 1 36

Zingrillo (22) 1996 20 6 Open 1–4 95Zingrillo (23) 1999 43 24 Open 1–4 93Cho (24) 2000 22 1–10 Open 1–6 64Del Prete (25) 2002 98 115 Open 1–4 94

a Near disappearance or marked (�50%) size reduction of cystic lesion.b Treated with simple aspiration.c Control group treated with saline.

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5776 J Clin Endocrinol Metab, December 2003, 88(12):5773–5777 Bennedbæk and Hegedus • Ethanol Sclerotherapy of Thyroid Cysts

roidectomy and in none in the saline group. However, sideeffects of ethanol instillation into cystic thyroid nodules seemto be few and are generally described as mild and transient,except for one case of respiratory distress and emergencysurgical treatment (31). In our experience, pain is less pro-nounced and of shorter duration than that described afterinjections into solid structures, and transient pain (durationof 10 min or less in six of seven patients) was only seen in 21%of patients treated with ethanol in the present study. Basedon these findings, it seems that there is no need for localanesthesia. 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 treatedwith larger thyroid cysts (25). Among the saline treatmentfailures referred for surgery, one patient needed reoperationdue to bleeding, but no further complications were encoun-tered in this group. Histology confirmed the pretreatmentcytological diagnosis in all but one patient, in whom a di-agnosis of a benign follicular adenoma was made.

Our study demonstrates that US-guided PEI with subse-quent complete aspiration is feasible, safe, and superior toflushing with isotonic saline. The technique is rapid and canbe performed on an outpatient basis. It is a clinically signif-icant alternative to surgery in recurrent thyroid cysts, pro-vided diagnostic biopsy results exclude malignancy.

Acknowledgments

We express our appreciation to pharmacist Leis Andersen for thepharmaceutical part of the study and to Lars Korsholm, statistician, forstatistical assistance.

Received June 10, 2003. Accepted August 21, 2003.Address all correspondence and requests for reprints to: Finn Noe

Bennedbæk, M.D., Ph.D., Department of Endocrinology M, Kloever-vaenget 6, Odense University Hospital, DK-5000 Odense C, Denmark.E-mail: finn.bennedbaek@ouh.fyns-amt.dk.

This work was supported by the Agnes and Knut Mørk Foundation,the A. P. Møller Support Foundation, and The Novo NordiskFoundation.

The results of this study were presented in part at the 85th AnnualMeeting of The Endocrine Society, Philadelphia, PA, 2003.

References

1. Mazzaferri EL 1993 Management of a solitary thyroid nodule. N Engl J Med328:553–559

2. McHenry CR, Slusarczyk SJ, Khiyami A 1999 Recommendations for man-agement of cystic thyroid disease. Surgery 126:1167–1171

3. Hammer M, Wortsman J, Folse R 1982 Cancer in cystic lesions of the thyroid.Arch Surg 117:1020–1023

4. los Santos ET, Keyhani-Rofagha S, Cunningham JJ, Mazzaferri EL 1990Cystic thyroid nodules. The dilemma of malignant lesions. Arch Intern Med150:1422–1427

5. Cusick EL, Mcintosh CA, Krukowski ZH, Matheson NA 1988 Cystic changeand neoplasia in isolated thyroid swellings. Br J Surg 75:982–983

6. Alexander EK, Heering JP, Benson CB, Frates MC, Doubilet PI, Cibas ES,Marqusee E 2002 Assessment of nondiagnostic ultrasound-guided fine needleaspirations of thyroid nodules. J Clin Endocrinol Metab 87:4924–4927

7. Gharib H 1994 Fine-needle aspiration biopsy of thyroid nodules: advantages,limitations, and effect. Mayo Clin Proc 69:44–49

8. Burch HB 1995 Evaluation and management of the solid thyroid nodule.Endocrinol Metab Clin North Am 24:663–710

9. Braga M, Cavalcanti TC, Collaco LM, Graf H 2001 Efficacy of ultrasound-guided fine-needle aspiration biopsy in the diagnosis of complex thyroidnodules. J Clin Endocrinol Metab 86:4089–4091

10. Clark OH, Okerlund MD, Cavalieri RR, Greenspan FS 1979 Diagnosis andtreatment of thyroid, parathyroid, and thyroglossal duct cysts. J Clin Endo-crinol Metab 48:983–988

11. Jensen F, Rasmussen SN 1976 The treatment of thyroid cysts by ultrasonicallyguided fine needle aspiration. Acta Chir Scand 142:209–211

12. Kuma K, Matsuzuka F, Yokozawa T, Miyauchi A, Sugawara M 1994 Fate ofuntreated benign thyroid nodules: results of long-term follow-up. World J Surg18:495–498

13. Bennedbaek FN, Hegedus L 2000 Management of the solitary thyroid nodule:results of a North American survey. J Clin Endocrinol Metab 85:2493–2498

14. Bennedbaek FN, Perrild H, Hegedus L 1999 Diagnosis and treatment of thesolitary thyroid nodule. Results of a European survey. Clin Endocrinol (Oxf)50:357–363

15. McCowen KD, Reed JW, Fariss BL 1980 The role of thyroid therapy in patientswith thyroid cysts. Am J Med 68:853–855

16. Hegedus L, Hansen JM, Karstrup S, Torp-Pedersen S, Juul N 1988 Tetracy-cline for sclerosis of thyroid cysts. A randomized study. Arch Intern Med148:1116–1118

17. Rozman B, Bence-Zigman Z, Tomic-Brzac H, Skreb F, Pavlinovic Z, Simo-novic I 1989 Sclerosation of thyroid cysts by ethanol. Periodicum Biologorum91:1116–1118

18. Yasuda K, Ozaki O, Sugino K, Yamashita T, Toshima K, Ito K, Harada T 1992Treatment of cystic lesions of the thyroid by ethanol instillation. World J Surg16:958–961

19. Monzani F, Lippi F, Goletti O, Del Guerra P, Caraccio N, Lippolis PV,Baschieri L, Pinchera A 1994 Percutaneous aspiration and ethanol sclerother-apy for thyroid cysts. J Clin Endocrinol Metab 78:800–802

20. Verde G, Papini E, Pacella CM, Gallotti C, Delpiano S, Strada S, FabbriniR, Bizzarri G, Rinaldi R, Panunzi C 1994 Ultrasound guided percutaneousethanol injection in the treatment of cystic thyroid nodules. Clin Endocrinol(Oxf) 41:719–724

21. Antonelli A, Campatelli A, Di Vito A, Alberti B, Baldi V, Salvioni G, FallahiP, Baschieri L 1994 Comparison between ethanol sclerotherapy and emptyingwith injection of saline in treatment of thyroid cysts. Clin Investig 72:971–974

22. Zingrillo M, Torlontano M, Ghiggi MR, D’Aloiso L, Nirchio V, Bisceglia M,Liuzzi A 1996 Percutaneous ethanol injection of large thyroid cystic nodules.Thyroid 6:403–408

23. Zingrillo M, Torlontano M, Chiarella R, Ghiggi MR, Nirchio V, Bisceglia M,Trischitta V 1999 Percutaneous ethanol injection may be a definitive treatmentfor symptomatic thyroid cystic nodules not treatable by surgery: five-yearfollow-up study. Thyroid 9:763–767

24. Cho YS, Lee HK, Ahn IM, Lim SM, Kim DH, Choi CG, Suh DC 2000Sonographically guided ethanol sclerotherapy for benign thyroid cysts: resultsin 22 patients. Am J Roentgen 174:213–216

25. Del Prete S, Caraglia M, Russo D, Vitale G, Giuberti G, Marra M,D’Alessandro AM, Lupoli G, Addeo R, Facchini G, Rossiello R, AbbruzzeseA, Capasso E 2002 Percutaneous ethanol injection efficacy in the treatment oflarge symptomatic thyroid cystic nodules: ten-year follow-up of a large series.Thyroid 12:815–821

26. Andersen S, Petersen SB, Laurberg P 2002 Iodine in drinking water in Den-mark is bound in humic substances. Eur J Endocrinol 147:663–670

27. Hegedus L, Perrild H, Poulsen LR, Andersen JR, Holm B, Schnohr P, JensenG, Hansen JM 1983 The determination of thyroid volume by ultrasound andits relationship to body-weight, age, and sex in normal subjects. J Clin Endo-crinol Metab 56:260–263

28. Hegedus L, Bonnema SJ, Bennedbaek FN 2003 Management of simple nod-ular goiter: current status and future perspectives. Endocr Rev 24:102–132

29. Bennedbaek FN, Karstrup S, Hegedus L 1997 Percutaneous ethanol injectiontherapy in the treatment of thyroid and parathyroid diseases. Eur J Endocrinol136:240–250

30. Bennedbaek FN, Hegedus L 1999 Percutaneous ethanol injection therapy inbenign solitary solid cold thyroid nodules: a randomized trial comparing oneinjection with three injections. Thyroid 9:225–233

31. Iacconi P, Spinelli C, Monzani F, Miccoli P 1996 Percutaneous injection forthyroid cysts: a word of caution. Clin Endocrinol (Oxf) 44:126

Bennedbæk and Hegedus • Ethanol Sclerotherapy of Thyroid Cysts J Clin Endocrinol Metab, December 2003, 88(12):5773–5777 5777