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  • 1. Treatment of Recurrent Thyroid Cysts with Ethanol: A Randomized Double-Blind Controlled Trial Finn Noe Bennedbæk and Laszlo Hegedüs J. Clin. Endocrinol. Metab. 2003 88: 5773-5777, doi: 10.1210/jc.2003-031000 To subscribe to Journal of Clinical Endocrinology & Metabolism or any of the other journals published by The Endocrine Society please go to: Copyright © The Endocrine Society. All rights reserved. Print ISSN: 0021-972X. Online
  • 2. 0021-972X/03/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 88(12):5773–5777 Printed in U.S.A. Copyright © 2003 by The Endocrine Society doi: 10.1210/jc.2003-031000 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- as a cyst volume <1 ml at the end of follow-up) was obtained sonography (US), 15–25% of solitary thyroid nodules are cystic in 27 of 33 [82%; confidence interval (CI), 65–93] patients or predominantly cystic, and most are benign. Simple aspi- treated with ethanol and in 16 of 33 (48%; CI, 31– 66) patients ration is the treatment of choice, but the recurrence rate is treated with saline (P 0.006). In the ethanol group, 21 of 33 10 – 80% depending on the number of aspirations and the cyst (64%) patients were cured after one session only, compared volume. The aim of this study was to evaluate the effect on with six of 33 (18%) in the saline group (P 0.002). The number recurrence rate of benign recurrent thyroid cysts in a double- of previous aspirations (P 0.005) and baseline cyst volume blind randomized study comparing ethanol instillation with (P 0.005) had influence on outcome, i.e. the chance of success instillation of isotonic saline and subsequent complete emp- decreased with the number of previous aspirations and with tying. Sixty-six consecutive patients with recurrent and be- increasing cyst volume. Seven patients (21%) treated with eth- nign (based on US-guided biopsy) thyroid cysts (>2 ml) were anol had moderate to severe pain (median duration, 5 min; CI, randomly assigned to either subtotal cyst aspiration, flushing 2–10), and one had transient dysphonia. Indirect laryngos- with 99% ethanol, and subsequent complete fluid aspiration copy was performed before and after the last session and was (n 33), or to subtotal cyst aspiration, flushing with isotonic normal in all patients. saline, and subsequent complete fluid aspiration (n 33). In We concluded that treatment of recurrent thyroid cysts case of recurrence (defined as cyst volume >1 ml) at the with ethanol is superior to simple aspiration and flushing monthly evaluations, the treatment was repeated but limited with saline and devoid of serious side effects. Our study dem- to a maximum of three treatments. Procedures were US- onstrates that flushing with ethanol is a clinically significant guided, and patients were followed for 6 months. Age, sex, nonsurgical alternative for thyroid cysts that recur despite number of previous aspirations, pretreatment cyst volume, repeat aspirations. (J Clin Endocrinol Metab 88: 5773–5777, and serum TSH did not differ in the two groups. Cure (defined 2003) N ODULAR THYROID DISEASE remains a common clinical problem; when evaluated by ultrasonogra- phy (US), 15–25% of solitary thyroid nodules are cystic or 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 predominantly cystic (1), and similarly, 18 –37% of all sur- ethanol instillation in thyroid cysts have been published gically excised thyroid nodules are cystic (2–5). The demon- (17–25). All report a high success rate, but only one placebo- stration of the cystic nature of a thyroid nodule does not rule controlled study with a short-term follow-up of 1 month in out malignancy (3, 5, 6). Most endocrinologists agree that a few patients is available (20). The aim of the present study reliance on fine-needle aspiration biopsy (FNAB) is essential was to determine whether US-guided ethanol injection re- for an optimal management strategy (1, 7, 8). To improve the duces the recurrence rate of benign thyroid cysts in a large- results of cytology, US-guided FNAB of the wall and solid scale, double-blind, randomized placebo-controlled study. portion of the cystic nodule along with cytology of the cystic fluid has been introduced and shown to improve the diag- Subjects and Methods nostic accuracy (9). In the case of a benign lesion, simple aspiration is the Subjects treatment of choice, but the recurrence rate is 10 – 80%, de- Eligible subjects included patients who were 20 –70 yr of age and had pending on the number of aspirations and the cyst volume a benign solitary cold palpable thyroid nodule causing local discomfort (10, 11). The fact that a number of benign cystic nodules and/or cosmetic complaints. Patients were referred by their primary care physicians. Inclusion criteria were: 1) [99mTc]pertechnetate scintig- resolve spontaneously, given sufficient time, makes therapy raphy demonstrating a solitary cold nodule; 2) US-demonstrated solitary superfluous in some (12). This is supported by results of two or prominent [additional nodule(s) 1 cm detected on US but not on the recent surveys in which 95 and 85%, respectively, of mem- scintiscan] anechoic cystic lesion with no or less than 10% solid com- bers of the American Thyroid Association and the European ponent and cyst volume at least 2 ml; 3) recurrence of the cyst fluid more Thyroid Association suggested a conservative, i.e. nonsur- than 1 month after primary aspiration; 4) cytological samples, obtained by FNAB under sonographic guidance, of the cyst fluid, the cyst wall gical, strategy for the benign solitary cystic thyroid nodule and, if present, a residual solid component, to rule out malignancy; 5) (13, 14). Provided a benign cytology, indications for therapy euthyroidism; 6) normal serum calcitonin; 7) no major concomitant are symptoms of compression or cosmetic complaints. There 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 bor- Abbreviations: FNAB, Fine-needle aspiration biopsy; PEI, percuta- derline-deficient iodine supply (26). The protocol was approved by the neous ethanol injection; US, ultrasonography. ethics committee of the county of Funen (journal no. 94/211) and the 5773
  • 3. 5774 J Clin Endocrinol Metab, December 2003, 88(12):5773–5777 Bennedbæk and Hegedus • Ethanol Sclerotherapy of Thyroid Cysts ¨ National Board of Health (journal no. 53123101994). All patients pro- 6-month evaluation of the last patient. Allocation of treatment was thus vided signed informed consent before randomization. carried out in an unbiased way. Sample size and statistical analysis Measurements Given a type I error of 0.05 (two-sided), a power of 90%, and an a priori US-guided FNAB ruled out malignancy in all patients, and only estimated clinically relevant difference of 40% gives a sample size of 34 results of cystic colloid goiter or colloid goiter were considered for patients in each group. The size of each group was thus predetermined. inclusion. In the case of nondiagnostic smears, FNAB was repeated, and Baseline variables were compared in the two treatment groups. Fre- if this was still nondiagnostic the patient was referred for surgery. The quencies are listed for dichotomous variables, and median (and quar- US examinations were performed using a LOGIQ 500 US scanner (GE tiles) are listed for ordered categorical and continuous variables. To Medical Systems, Milwaukee, WI) with a 12-MHz linear transducer evaluate the differences, we used the standard 2 test for dichotomous (type 739L) mounted with a needle steering device for precise US-guided variables, and for ordered categorical and continuous variables we used punctures. The total thyroid volume (normal range, 9.6 –27.6 ml) was the Wilcoxon rank sum test. calculated on the basis of an ultrasonic scanning procedure using a The difference between the two treatment groups was evaluated by 5.5-MHz compound scanner (type 1846, Bruel and Kjær, Naerum, Den- ¨ an odds ratio with confidence intervals and associated with a P value mark) (27). For each patient, US measurements were performed by the obtained from logistic regression. To evaluate whether the findings were same operator with blinding toward previous measurements. stable against the possible influence of other variables, we performed a Blood tests included serum total T4 (normal range, 65–135 nmol/liter) multiple logistic regression with listing of odds ratios, confidence in- determined by RIA (Diagnostic Products Corp., Los Angeles, CA), se- tervals, and P values. rum total T3 (normal range, 1.00 –2.10 nmol/liter) determined by RIA Two of the 68 patients were excluded due to technical difficulties in (Johnson & Johnson, Clinical Diagnostics Ltd., Amersham, UK), serum one and due to pain during the instillation procedure and therefore calcitonin (normal range, 0 – 0.10 g/liter) determined by RIA (MediLab, discontinuation of the treatment in the other. Not until the end of the Copenhagen, Denmark), and serum TSH (normal range, 0.30 – 4.0 mU/ study when the sealed code was broken was it established that one of liter) determined by DELFIA (Wallac Oy, Turku, Finland). Free T4 and the two excluded patients had been treated with saline and the other T3 indices were calculated by multiplying serum T4 and T3 levels by the with ethanol. percentage T3 resin uptake. Serum antithyroid peroxidase antibodies The computer programs used were STATA statistical software (Stata (normal range 200 U/ml) were determined by RIA DYNO test Corporation, College Station, TX), release 7.0, 2001, and SPSS 11.5 (SPSS (Brahms Diagnostica, Berlin, Germany). Only patients with normal se- Inc., Chicago, IL). rum calcitonin, thyroid hormone, and TSH levels were considered for inclusion. Results Pretreatment findings Study design and treatment Clinical data for the 66 consecutive patients are given in Random allocation was achieved using a random number generator on a computer. Patients were assigned to 1) subtotal cyst aspiration, Table 1. All patients were treated 4 –12 wk after the last instillation and flushing with 99% ethanol, and subsequent complete recurrence. The groups were similar regarding sex, age, nod- fluid aspiration (without removing the needle) after 2 min and under ule duration, and the number of recurrences after previous continuous US control; or 2) subtotal cyst aspiration, instillation and aspirations. Likewise, there were no statistical differences flushing with isotonic saline, and subsequent complete fluid aspiration (without removing the needle) after 2 min and under continuous US regarding the number of pure cysts, cysts with a minor solid control. After subtotal aspiration of the cyst, the syringe was detached, component, and the presence of additional small nodules or the needle left in situ, and a different syringe and needle were used for volume estimates in the two treatment groups. Serum TSH aspiration from the bottle. The aim was an ethanol or saline dose of one values were similar; serum free T4 and free T3 indices were fourth to one half of the aspirated cyst fluid volume. slightly lower in the saline group, but we consider this find- All patients were evaluated before and after 1, 2, 3, and 6 months (calculated from the last treatment session in case of recurrence, and ing of no clinical significance. therefore a need of a second or third treatment). Measurements included serum thyroid hormones and TSH, as well as thyroid cyst volume and Treatment response (Tables 2 and 3) total thyroid volume assessed by US. In case of recurrence (US-deter- mined cyst volume 1 ml), treatment was repeated at the 1-month The median treatment volume given was 3.5 ml [quartiles, evaluation, and patients were submitted to a maximum of three treat- 2;5] in the percutaneous ethanol injection (PEI) group com- ments. In case of a fourth recurrence, patients were offered hemithy- pared with 3.0 ml [2;5] in the saline (NaCl) group corre- roidectomy, and the 1-month evaluation after the third and last treat- ment represented the end-point for these patients. In case of success, data sponding to 36% of the cyst volume in each group (P 0.4). from the 6-month evaluation were used in the evaluation of the efficacy Treatment response differs markedly based on the median of the treatment. number of treatments given: 1 [1;2] in the PEI group com- At the last visit, patients were asked to rate their present pressure pared with 3 [2;3] in the saline group (P 0.0002). A total of symptoms and cosmetic complaints as present or absent (dichotomous data). 27 patients (82%) treated with PEI were cured, 21 of whom The study was carried out with complete blinding of both investi- (78%) were cured after only one treatment, compared with gators (F.N.B. and L.H.) and patients. The Pharmacy of Odense Uni- a total of 16 patients (48%) treated with saline, six of whom versity Hospital (Centralapoteket OUH) was responsible for the pro- (38%) were cured after one treatment—a highly significant duction of absolute ethanol (800 mg/ml) and isotonic saline, for difference between the two treatment groups (P 0.006). preparation of bottles labeled “project ethanol vs. saline,” and for pro- viding sealed code lists. A pharmacist independent of the investigators Failure, on the other hand, was seen in six (18%) in the PEI provided the investigators with 68 sealed boxes (labeled patient no. 1, group compared with 17 (52%) in the saline group. A priori 2, etc.). Each box contained three sealed bottles with 10 ml of sterile fluid failure was defined as a cyst volume of more than 1 ml, and (34 3 with saline and 34 3 with ethanol), and each was labeled this was chosen on clinical grounds as a volume reduction “project medicine.” The corresponding list with codes detailing the content of the bottles was stored in a sealed envelope at the pharmacy. from e.g. 20 to 8 ml; this may represent a statistically signif- Complete blinding was maintained throughout the whole study period, icant change but not necessarily a clinically relevant change and the sealed envelope with treatment codes was not broken until the that is satisfactory for the patient. The median reduction in
  • 4. Bennedbæk and Hegedus • Ethanol Sclerotherapy of Thyroid Cysts ¨ J Clin Endocrinol Metab, December 2003, 88(12):5773–5777 5775 TABLE 1. Baseline characteristics in the two treatment groups Variable PEI NaCl P Sex (M/F) 4/29 7/26 0.3 Age (yr) 48 [33;57] 46 [40;53] 0.9 Previous surgery/131-I 2 4 0.3 Months from diagnosis 9 [4;12] 7 [4;13] 0.8 Previous number of aspirations 1 [1;2] 1 [1;2] 0.6 US findings Solitary cyst 26 26 1 Solitary and predominantly cystic 7 7 Solitary lesion 23 24 0.98 Additional small nodules 10 9 Cyst volume (ml) 8.0 [5;14] 8.0 [4;15] 0.8 Thyroid volume (ml) 26 [20;35] 32 [18;42] 0.5 Cyst fluid appearance Clear/yellow 13 11 0.6 Bloody/brownish 20 22 Biochemical measurements TSH (mU/liter) (normal, 0.3– 4) 0.95 [0.6;1.4] 0.95 [0.7;1.1] 0.85 FT4-I (U/liter) (normal, 60 –140) 102 [88;116] 88 [79;100] 0.02 FT3-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] 0.4 No. of treatments 1 [1;2] 3 [2;3] 0.0002 Cure after 1 treatment 21 6 2 treatments 4 7 0.006 3 treatments 2 3 Failure 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 Multivariate effects on treatment success Variable Univariate OR OR P CI Ethanol vs. saline 27.752 0.005 2.699 285.357 4.781 Previous aspirations 0.058 0.005 0.008 0.419 0.380 Gender 2.435 0.524 0.157 37.740 0.373 Age 1.026 0.561 0.940 1.121 0.969 Months from diagnosis 1.039 0.179 0.983 1.098 0.987 Cystic vs. complex 0.855 0.873 0.125 5.867 0.648 Additional nodules 7.820 0.127 0.559 109.432 0.344 Cyst volume 0.830 0.005 0.728 0.945 0.886 Thyroid volume 0.921 0.052 0.847 1.001 0.951 OR, Odds ratio; CI, confidence interval. cyst volume was 100% [83;100] in the PEI group, compared 0.05). Age and US findings (cystic vs. complex) do not in- with 68% [21;94] in the saline group (P 0.001). Results from fluence outcome. the 3- and 6-month evaluations did not differ. The presence or absence of pressure symptoms and/or As seen in Table 3, the number of previous aspirations cosmetic complaints at the end of follow-up correlated in all influences the success rate, i.e. the higher the number of but one of the 66 patients to the a priori chosen cut-off limit previous aspirations, the smaller the chance of treatment of a cyst volume larger or smaller than 1 ml. success (P 0.005). Gender does not influence outcome, but there is a nonsignificant trend toward female sex being ad- Side effects vantageous. Likewise, there is a trend toward nodule dura- tion and also the presence of additional nodules influencing Seven patients (21%) in the ethanol group reported tran- the chance of success. Pretreatment cyst volume, however, sient pain/tenderness, with a duration of 10 min or less in six does influence the chance of success, i.e. having smaller cysts patients and 1 h in one patient. Only one patient in the saline being advantageous (P 0.005), whereas total thyroid vol- group reported pain lasting for 10 min after treatment. One ume has only a borderline-significant effect on outcome (P patient in the PEI group had transient dysphonia lasting for
  • 5. 5776 J Clin Endocrinol Metab, December 2003, 88(12):5773–5777 Bennedbæk and Hegedus • Ethanol Sclerotherapy of Thyroid Cysts ¨ 1 h, but all patients, including the latter, had a normal indirect an open study with a control group, 26 patients treated with laryngoscopy after treatment. Due to treatment failure, a one to five ethanol instillations had a 77% success rate, but hemithyroidectomy was subsequently performed in all six the control group treated with saline underwent only one patients treated with PEI; in one of these patients, the sur- treatment, hampering the evaluation owing to the fact that geon described periglandular fibrosis making the surgical repeated treatments with saline will also increase the cure procedure more difficult but causing no complications. No rate (21). In larger and symptomatic thyroid cysts, the treat- further side effects were encountered, and thyroid function ment also seems effective as shown in a study comprising 43 remained unaltered throughout the entire period of fol- selected patients with a mean volume of 38 ml showing a low-up (data not given). Among the saline treatment failures success rate (near disappearance or 50% reduction) of 93% (n 17), all were offered surgery according to the protocol, after 2 yr (23). In a recent large-scale study of 98 patients, one but seven refused surgery and were offered follow-up with third of the cysts were larger than 40 ml, and only six patients repeat aspiration or treatment with PEI. Ten patients were with an initial response to PEI relapsed during a mean fol- thus referred for surgery (hemithyroidectomy). The proce- low-up of 10 yr (25). Transient pain was reported by 71% of dure was uncomplicated in all except for postoperative patients and dysphonia lasting for 1 yr in one patient, but no bleeding in one patient necessitating reoperation, but no further side effects were reported in this study (25). periglandular fibrosis was described. Our study shows that PEI sclerotherapy reduces recur- rence rate of thyroid cysts relapsed after evacuation alone Discussion and that cure was obtained in 64% of patients after one Fine-needle aspiration of cystic thyroid nodules is a com- treatment only and in 82% overall. This contrasts with the mon cause of nondiagnostic rather than false-negative re- 48% who were cured after simple aspiration and flushing sults. Recommendations for treatment should be based on with saline, of whom only 18% were cured by one treatment. cytological results or failure of cyst resolution alone (2). Al- Although a definition of failure as a thyroid cyst volume of though aspiration may be of therapeutic value, the reported 1 ml seems rigorous, it is based on clinical grounds. In most efficacy varies considerably (28). The success rate largely published studies on PEI in thyroid cysts, a success rate is depends on the cyst volume and the number of previous defined as near disappearance or marked ( 50%) size re- aspirations. duction of the cystic lesion. In our experience, most cystic In benign nodular thyroid disease, PEI has been intro- nodules vary in size, and although size reduction is often duced as an alternative to surgery (cold or hot nodules) or seen during follow-up of cysts primarily evacuated, they radioiodine therapy (hot nodules) (29). In benign cystic thy- tend to increase gradually given enough time. roid nodules this technique was introduced in 1989, and The technique used by us is flushing with absolute ethanol published studies comprise 345 patients with a cystic thyroid ( 99%) in an amount of 25–50% of the cyst volume (maxi- nodule treated with PEI (Table 4). The success rate, defined mum 10 ml), preceded by a submaximal aspiration ( 90%) as near disappearance or marked ( 50%) size reduction, of the cyst fluid under US guidance. Ethanol is left in place varies from 72 to 95%. In the only placebo-controlled study for 2 min, and subsequently a complete aspiration is per- with only one treatment, the short-term (1 month) success formed. As opposed to the technique described in the pub- rate in 10 patients was 80% in the group treated with ethanol lished studies on PEI in thyroid cysts, we recommend sub- and 30% in the group treated with simple aspiration (20). sequent complete aspiration of ethanol. It is important to Long-term follow-up (12 months) in 32 consecutive patients recognize that each ethanol injection carries a risk of ethanol treated once with ethanol confirms the preliminary results escaping outside the capsule, inducing paraglandular fibro- obtained in the smaller randomized study (20). The remain- sis as described in patients with solid cold thyroid nodules ing studies lack an evaluation of success rate based on num- treated with PEI (30). This was seen in one of six patients with ber of ethanol instillations and an adequate control group. In relapse in the PEI group subjected to subsequent hemithy- TABLE 4. PEI in cystic thyroid nodules: listing of published studies Yr of No. of patients Follow-up No. of Success ratea Author Study design publication treated (months) treatments (%) Rozman (17) 1989 13 8 Open 1 77 Yasuda (18) 1992 61 6 Open 1– 4 72 Monzani (19) 1994 20 12 Open 1–2 95 Verde (20) 1994 10 10b 1 1 } Randomized 1 1 80 30 32 12 Open 1 80 Antonelli (21) Zingrillo (22) 1994 1996 26 44c 20 12 12 6 } Open Open 1–5 1 1– 4 77 36 95 Zingrillo (23) 1999 43 24 Open 1– 4 93 Cho (24) 2000 22 1–10 Open 1– 6 64 Del 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.
  • 6. Bennedbæk and Hegedus • Ethanol Sclerotherapy of Thyroid Cysts ¨ J Clin Endocrinol Metab, December 2003, 88(12):5773–5777 5777 roidectomy and in none in the saline group. However, side 7. Gharib H 1994 Fine-needle aspiration biopsy of thyroid nodules: advantages, limitations, and effect. Mayo Clin Proc 69:44 – 49 effects of ethanol instillation into cystic thyroid nodules seem 8. Burch HB 1995 Evaluation and management of the solid thyroid nodule. to be few and are generally described as mild and transient, Endocrinol Metab Clin North Am 24:663–710 except for one case of respiratory distress and emergency 9. Braga M, Cavalcanti TC, Collaco LM, Graf H 2001 Efficacy of ultrasound- guided fine-needle aspiration biopsy in the diagnosis of complex thyroid surgical treatment (31). In our experience, pain is less pro- nodules. J Clin Endocrinol Metab 86:4089 – 4091 nounced and of shorter duration than that described after 10. Clark OH, Okerlund MD, Cavalieri RR, Greenspan FS 1979 Diagnosis and injections into solid structures, and transient pain (duration treatment of thyroid, parathyroid, and thyroglossal duct cysts. J Clin Endo- crinol Metab 48:983–988 of 10 min or less in six of seven patients) was only seen in 21% 11. Jensen F, Rasmussen SN 1976 The treatment of thyroid cysts by ultrasonically of patients treated with ethanol in the present study. Based guided fine needle aspiration. Acta Chir Scand 142:209 –211 12. Kuma K, Matsuzuka F, Yokozawa T, Miyauchi A, Sugawara M 1994 Fate of on these findings, it seems that there is no need for local untreated benign thyroid nodules: results of long-term follow-up. World J Surg anesthesia. This is supported by the study by Zingrillo et al. 18:495– 498 (23) reporting a mild transient pain/“burning sensation” 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 radiating to the ear or neck in 12% of the treatment sessions, 14. Bennedbaek FN, Perrild H, Hegedus L 1999 Diagnosis and treatment of the ¨ although a higher rate (71%) was observed in patients treated solitary thyroid nodule. Results of a European survey. Clin Endocrinol (Oxf) with larger thyroid cysts (25). Among the saline treatment 50:357–363 15. McCowen KD, Reed JW, Fariss BL 1980 The role of thyroid therapy in patients failures referred for surgery, one patient needed reoperation with thyroid cysts. Am J Med 68:853– 855 due to bleeding, but no further complications were encoun- 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 Med tered in this group. Histology confirmed the pretreatment 148:1116 –1118 cytological diagnosis in all but one patient, in whom a di- 17. Rozman B, Bence-Zigman Z, Tomic-Brzac H, Skreb F, Pavlinovic Z, Simo- agnosis of a benign follicular adenoma was made. novic I 1989 Sclerosation of thyroid cysts by ethanol. Periodicum Biologorum 91:1116 –1118 Our study demonstrates that US-guided PEI with subse- 18. Yasuda K, Ozaki O, Sugino K, Yamashita T, Toshima K, Ito K, Harada T 1992 quent complete aspiration is feasible, safe, and superior to Treatment of cystic lesions of the thyroid by ethanol instillation. World J Surg flushing with isotonic saline. The technique is rapid and can 16:958 –961 19. Monzani F, Lippi F, Goletti O, Del Guerra P, Caraccio N, Lippolis PV, be performed on an outpatient basis. It is a clinically signif- Baschieri L, Pinchera A 1994 Percutaneous aspiration and ethanol sclerother- icant alternative to surgery in recurrent thyroid cysts, pro- apy for thyroid cysts. J Clin Endocrinol Metab 78:800 – 802 20. Verde G, Papini E, Pacella CM, Gallotti C, Delpiano S, Strada S, Fabbrini vided diagnostic biopsy results exclude malignancy. R, Bizzarri G, Rinaldi R, Panunzi C 1994 Ultrasound guided percutaneous ethanol injection in the treatment of cystic thyroid nodules. Clin Endocrinol Acknowledgments (Oxf) 41:719 –724 21. Antonelli A, Campatelli A, Di Vito A, Alberti B, Baldi V, Salvioni G, Fallahi We express our appreciation to pharmacist Leis Andersen for the P, Baschieri L 1994 Comparison between ethanol sclerotherapy and emptying pharmaceutical part of the study and to Lars Korsholm, statistician, for with injection of saline in treatment of thyroid cysts. Clin Investig 72:971–974 statistical assistance. 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 Received June 10, 2003. Accepted August 21, 2003. 23. Zingrillo M, Torlontano M, Chiarella R, Ghiggi MR, Nirchio V, Bisceglia M, Address all correspondence and requests for reprints to: Finn Noe Trischitta V 1999 Percutaneous ethanol injection may be a definitive treatment Bennedbæk, M.D., Ph.D., Department of Endocrinology M, Kloever- for symptomatic thyroid cystic nodules not treatable by surgery: five-year vaenget 6, Odense University Hospital, DK-5000 Odense C, Denmark. follow-up study. Thyroid 9:763–767 E-mail: 24. Cho YS, Lee HK, Ahn IM, Lim SM, Kim DH, Choi CG, Suh DC 2000 This work was supported by the Agnes and Knut Mørk Foundation, Sonographically guided ethanol sclerotherapy for benign thyroid cysts: results in 22 patients. Am J Roentgen 174:213–216 the A. P. Møller Support Foundation, and The Novo Nordisk 25. Del Prete S, Caraglia M, Russo D, Vitale G, Giuberti G, Marra M, Foundation. D’Alessandro AM, Lupoli G, Addeo R, Facchini G, Rossiello R, Abbruzzese The results of this study were presented in part at the 85th Annual A, Capasso E 2002 Percutaneous ethanol injection efficacy in the treatment of Meeting of The Endocrine Society, Philadelphia, PA, 2003. large symptomatic thyroid cystic nodules: ten-year follow-up of a large series. Thyroid 12:815– 821 References 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 1. Mazzaferri EL 1993 Management of a solitary thyroid nodule. N Engl J Med 27. Hegedus L, Perrild H, Poulsen LR, Andersen JR, Holm B, Schnohr P, Jensen ¨ 328:553–559 G, Hansen JM 1983 The determination of thyroid volume by ultrasound and 2. McHenry CR, Slusarczyk SJ, Khiyami A 1999 Recommendations for man- its relationship to body-weight, age, and sex in normal subjects. J Clin Endo- agement of cystic thyroid disease. 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Alexander EK, Heering JP, Benson CB, Frates MC, Doubilet PI, Cibas ES, injection with three injections. Thyroid 9:225–233 Marqusee E 2002 Assessment of nondiagnostic ultrasound-guided fine needle 31. Iacconi P, Spinelli C, Monzani F, Miccoli P 1996 Percutaneous injection for aspirations of thyroid nodules. J Clin Endocrinol Metab 87:4924 – 4927 thyroid cysts: a word of caution. Clin Endocrinol (Oxf) 44:126