Helle Døssing, Finn Noe Bennedbæk, and Laszlo Hegedüs

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1 JCEM ONLINE Brief Report Endocrine Care Interstitial Laser Photocoagulation (ILP) of Benign Cystic Thyroid Nodules A Prospective Randomized Trial Helle Døssing, Finn Noe Bennedbæk, and Laszlo Hegedüs Department of Otorhinolaryngology and Neck Surgery (H.D.), Odense University Hospital, DK-5000 Odense C, Denmark; Department of Endocrinology and Metabolism (F.N.B.), Herlev University Hospital, DK-2730 Herlev, Denmark; and Department of Endocrinology and Metabolism (H.D., L.H.), Odense University Hospital, DK-5000 Odense C, Denmark Context: Recurrence rate, after aspiration, in cystic thyroid nodules is very high. Interstitial laser photocoagulation (ILP) is a minimally invasive procedure that reduces the need for surgery in patients with a benign solid thyroid nodule. Objective: The aim of the study was to evaluate the efficacy of ILP on remission rates in recurrent, predominantly cystic thyroid nodules. Design and Methods: Forty-four consecutive outpatients with a symptomatic, recurrent, and cytologically benign cystic (cyst volume 2 ml) thyroid nodule were randomized to a single aspiration with (n 22) or without (n 22) subsequent ILP and followed up after 1, 3, and 6 months. Results: Successful outcome (cyst volume 1 ml) was obtained in 15 of 22 (68%) patients in the ILP group, compared to 4 of 22 (18%) in the aspiration group (P.002). In the ILP group, the solid part of the nodule was reduced from a median of 1.8 to 1.0 ml (P.02). In the aspiration-alone group, neither the cyst volume nor the solid nodule volume was significantly reduced. The reduction in median visual analog score (0 10 cm) for pressure symptoms was significantly higher in the ILP group (from 3.0 to 0.0 cm) than in the aspiration-alone group (from 4.0 to 3.5 cm) (P.006, between groups). No major side effects occurred, and thyroid function was unaffected throughout. Conclusions: US-guided aspiration and subsequent ILP of benign recurrent predominantly cystic thyroid nodules is safe. It significantly reduces recurrence rate, the volume of the solid nodule component, and pressure symptoms. ILP constitutes an important alternative to surgery in such patients. (J Clin Endocrinol Metab 98: E1213 E1217, 2013) Thyroid nodules are common in the adult population, and approximately 85% of these are nonfunctioning (1). According to several studies, 15 30% of thyroid nodules are cystic or predominantly cystic. The incidence of thyroid cancer in cystic nodules is low, and the vast majority of thyroid cancers are solid or have a minimal (1 5%) cystic component at ultrasonography (US) (2). Use of US-guided fine-needle aspiration is mandatory and improves the diagnostic accuracy (3). ISSN Print X ISSN Online Printed in U.S.A. Copyright 2013 by The Endocrine Society Received February 26, Accepted May 6, First Published Online June 18, 2013 Aspiration of the cystic part may reduce the pressurerelated symptoms, but the recurrence rate is up to 80%, depending on the number of aspirations and the cyst volume (4). In randomized studies, tetracycline did not improve remission rates (5), whereas ethanol greatly improved rates (6), as acknowledged in recent guidelines (7). As an alternative to surgery and a way to reduce the side effects associated with ethanol sclerotherapy (4), interstitial laser photocoagulation (ILP) has, in randomized studies, shown promising results in solid benign thyroid nod- Abbreviations: ILP, interstitial laser photocoagulation; PEI, percutaneous ethanol injection; US, ultrasonography. doi: /jc J Clin Endocrinol Metab, July 2013, 98(7):E1213 E1217 jcem.endojournals.org E1213

2 E1214 Døssing et al Laser Therapy of Thyroid Cysts J Clin Endocrinol Metab, July 2013, 98(7):E1213 E1217 ules (8 10). The aim of this study was to follow up on our pilot study (11) and evaluate the remission rate in patients with a recurrent benign predominantly cystic thyroid nodule randomized to aspiration, with or without subsequent ILP. Patients and Methods Given a type I error of 0.05, a power of 90%, and a minimal relevant difference of 46% (6), 22 patients are required in each group. The patients (30 females and 14 males; median age, 49 y; range, y) were referred due to a palpable symptomatic thyroid nodule and randomized without stratification for nodule size. All patients had a benign cold solitary cystic-solid thyroid nodule evaluated clinically, scintigraphically, and by US-guided fine-needle aspiration. Specimens of the solid parts and centrifugates of the cyst fluids were compatible with cystic colloid goiters, as evaluated by an experienced cytopathologist. All had recurrence of the cystic part after the initial diagnostic aspiration. Clinically, there was neither suspicion of thyroid cancer nor a family history of it. All patients were euthyroid and had normal serum calcitonin. Blood tests included serum TSH (normal range, mu/ml), serum total T 4 (normal range, mmol/l), and serum total T 3 (normal range, mmol/l). At enrollment, which was at least 1 month after the previous aspiration (Table 1), and at the 6-month evaluation, the patients were asked to rate pressure symptoms and cosmetic complaints on a visual analog scale (0 10 cm). ILP was carried out on an outpatient basis. The patients were investigated 1, 3, and 6 months after the treatment. Initially and during the follow-up, cyst volume, volume of the solid part and total thyroid volume, as well as thyroid function, were investigated. The volume of the nodules was calculated by measuring the 3 largest perpendicular diameters (length width depth /6). Recurrence of the cystic part was defined as the presence of more than 1 ml (determined by US or aspiration). The initial cyst volume was calculated by US, and this result was compared with the aspirated volume. US examinations were performed using a Logiq 500 (GE Medical Systems, Milwaukee, Wisconsin) with a 12-MHz linear transducer (type 739L) mounted with a needle-steering device for precise US-guided punctures. Under sterile conditions and guided by US, the laser fiber (0.4 mm in diameter) was positioned in the thyroid nodule through the lumen of an 18-gauge (1.2-mm) needle and preceded by local anesthesia with lidocaine (10 mg/ml). Guided by US, the steering needle was positioned in the cystic part of the thyroid nodule. When this was completely aspirated, and under continuoususguidance, thesteeringneedlewasleftinsitu, andthelaser fiber was positioned in order to induce necrosis and destroy the cyst membrane and the solid part of the nodule. The output power, provided from a continuous-wave infrared (820 nm) diode laser (model 15; Diomed, Cambridge, United Kingdom), was between 2.0 and 3.0 W (mean, 2.5 W), dependent on the size of the solid part of the nodule. The vapor was clearly visible on US as an irregular hyperechogenic area enlarging over time. The procedure was terminated when this area was stationary in size and flow signs in the treated areas, evaluated by color Doppler, were absent. Typically, 1 to 3 areas were treated (dependent on the size and accessibility of the solid part) before the procedure was terminated. US measurements were performed by the same investigator (H.D.) with blinding toward the previous measurements. The protocol was approved by the ethics committee of the county of Funen (journal no ). All patients provided signed informed consent before inclusion. Statistics Results for continuous data are given as medians and quartiles. Within-group changes were assessed by Friedman s test or by Wilcoxon signed ranks test. A Mann-Whitney test was used to compare data between groups, and Fisher s exact test was used to analyze differences in outcome. A backward step-wise logistic Table 1. Characteristics of the 2 Treatment Groups Variable Aspiration Laser Treatment P Value Baseline Age, y 49 (40; 56) 49 (39; 56).82 No. of males/females 9/13 5/17.20 Months since diagnosis 7.5 (5.0; 12.0) 12.0 (6.0; 18.0).2 No. of previous aspirations 2 (1; 2) 2 (1; 2).40 US findings Pure cyst Cystic/solid Total nodule volume, ml 10.0 (5.6; 22.0) 11.8 (5.8; 26.8).72 Cyst volume, ml 8.8 (4.8; 22.0) 10.8 (3.5; 26.8).90 TSH, mu/l 1.12 (0.78; 1.47) 1.10 (0.79; 1.51).85 Anti-TPOAb (negative/positive) 21/1 21/1 1.0 Outcome at 6 months Cured/recurrence 4/18 (18%) 15/7 (68%).002 Total nodule volume reduction, % 28 (0; 67) 73 (39; 90).001 Cyst volume reduction, % 32 (0; 72) 94 (60; 100).007 Reduction of solid part, % 0 ( 10; 7) 54 (9; 75).02 TSH, mu/l 1.15 (1.09; 1.15) 0.94 (0.80; 1.87).12 Anti-TPOAb (negative/positive) 21/1 21/1 1.0 Abbreviation: TPOAb, thyroid peroxidase antibody. Values represent median (quartile) or number of cases. Cure of the cystic part was defined as a volume less than 1 ml. TSH normal value, mu/ml.

3 doi: /jc jcem.endojournals.org E1215 Figure 1. Pressure symptoms and cosmetic complaints, initially and at the final examination 6 months after therapy, evaluated on a visual analog scale from 0 to 10 cm. regression was employed for analyzing potential variables predictive for outcome. A P value.05 was considered significant. The statistical analyses were performed using the SPSS statistical software, version 20.0 (SPSS, Chicago, Illinois). Results Clinical data for the 44 randomized patients are given in Table 1. The groups were similar regarding all pertinent pretreatment variables, and none had elevated levels of serum calcitonin. [ 99m Tc] pertechnetate scintigraphy showed a solitary low uptake area compatible with a solitary cyst or a predominantly cystic nodule, subsequently verified by US. US-guided cytology was benign in all subjects. There was no statistically significant difference in pretreatment self-reported pressure symptoms (Figure 1). Cosmetic complaints were minor in both groups and were less pronounced in the aspiration-alone group compared to the ILP group (P.06). Table 2. Multivariate Analysis of Variables Affecting Treatment Success (Logistic Regression) Variable Odds Ratio Confidence Interval P Value ILP vs aspiration , Previous aspiration a , Gender , Months from diagnosis , Baseline nodule volume , Baseline cyst volume , a Number of aspirations before inclusion. Outcome (Tables 1 and 2) In the ILP group, remission of the cystic part was obtained in 15 of 22 (68%) patients, compared with 4 of 22 (18%) patients treated with aspiration alone (P.002). Median (quartile) total nodule volume in the aspiration-alone group was reduced from 10.0 ml (5.6; 2.0) to 6.0 ml (3.4; 17.2), corresponding to a median reduction of 26% (0; 67) (P.07). In the ILP group, the median total nodule volume was reduced from 11.8 ml (5.8; 26.8) to 2.5 ml (0.9; 8.3), corresponding to a median reduction of 73% (39; 93) (P.001). There was no significant difference between the group (P.001). In the aspiration-alone group, median cyst volume was reduced from 8.8 ml (4.8; 22.0) to 4.0 ml (2.1; 16.0), corresponding to a reduction of 32% (0; 72) (P.17), compared to a reduction from 10.8 ml (3.5; 26.8) to 0.3 ml (0; 7.1) in the ILP group, corresponding to a reduction of 98% (60; 100) (P.001). The volume of the solid part was reduced from a median of 2.5 ml (1.0; 3.8) to 1.0 ml (0.0; 1.8) (P.04) in the ILP group. In the aspiration group, the pretreatment median volume of the solid part was 2.6 ml (0.6; 6.3) and at the final evaluation, 3.0 ml (0.6; 4.9) (P.5). The only parameters affecting treatment success were the ILP therapy (P.002) and the number of aspirations before inclusion, in that a higher number of aspirations decreased the chance of success (P.03; Table 2). According to self-estimated ratings on a visual analog scale from 0 to 10, median pressure symptoms in the ILP group were reduced from 3.5 (2.0; 6.0) to 0 (0.0; 3.0) (P.03), and cosmetic complaints were reduced from 1 (0.0; 5.0) to 0 (0.0; 0.25) (P.003). In the aspiration-alone group, neither median pressure symptoms (from 4.25 [2.5; 5.0] to 4.0 [1; 5.25]; P.22) nor cosmetic complaints (from 0 [0.0; 1.5] to 0 [0; 0]; P.5; Figure 1) were significantly reduced. Eleven patients in the ILP group reported slight to moderate pain with a median duration of 2 days (0; 5), necessitating mild analgesics in 8 patients. There were no laryngeal nerve injuries (documented by post-treatment indirect laryngoscopy in all), and thyroid function remained unaltered throughout (Table 1). Fourteen patients in the aspiration-alone group with cyst recurrence were subsequently offered ILP, 10 of whom were cured.

4 E1216 Døssing et al Laser Therapy of Thyroid Cysts J Clin Endocrinol Metab, July 2013, 98(7):E1213 E1217 Subsequently, 9 patients with insufficient treatment outcome (5 from the aspiration-alone group and 4 from the ILP group) had thyroid surgery, all of whom had benign histology. The median ILP treatment duration was 600 seconds (420; 600). The median total energy delivered was 1272 J (990; 1500), corresponding to 83 J (49; 224) per milliliter of nodule tissue. Discussion In cystic thyroid nodules, aspiration alone may be of therapeutic value, but the effect varies considerably, and recurrence is very prevalent (1). In a randomized study, percutaneous ethanol injection (PEI) achieved remission in 68% of cystic thyroid nodules after 1 injection (12). The limitations and disadvantages of PEI therapy are related to the difficulty in predicting the diffusion of the ethanol, especially in solid parts of the nodule. Furthermore, side effects related to ethanol seepage outside the capsule may cause pronounced pain or more serious side effects such as paresis of the vocal cords or extraglandular fibrosis, which may impede subsequent surgery in case of treatment failure (4, 6). During the latest decade, ILP has successfully been introduced as an alternative to surgery in benign nodular thyroid disease (1, 13). It is efficacious in autonomous thyroid nodules (14), more so in nonfunctioning thyroid nodules (8 10, 15), also in the long term (10, 16), and it has recently also been suggested for treating locoregional metastatic papillary thyroid cancer (17). It is considered a minimally invasive, safe, and well-tolerated procedure (8 10, 16), the main shortcomings being availability, considerable operator dependence, and the lack of randomized studies comparing nonsurgical treatments head on (18). An advantage of ILP is the precision in inducing a welldefined area of tissue ablation in a reproducible way. ILP is effective in inducing necrosis and subsequent thyroid nodule shrinkage of 50% in the vast majority, dependent on the number of sessions and energy used (9, 13, 16). Damage is restricted to the ablated area without extranodular tissue damage. Based on the above and the 80% cure rate (8 of 10 patients) in our pilot study (11), it was logical to test ILP in a randomized prospective study in recurrent solitary predominantly cystic thyroid nodules. The marginally lower (68%) cure rate in the present study is best explained by a smaller sample size and the smaller cyst size in the pilot study. Efficacy was highly significantly better than with aspiration alone (18%) and was congruent with that obtained with PEI (12). As opposed to PEI, no extranodular damage was observed, and pain was milder, whereas the reduction of the solid nodule component was preserved, and self-evaluated pressure symptoms vanished in the vast majority. In a retrospective nonrandomized study, radiofrequency ablation performed similar to PEI but took longer and was considerably more expensive (19). We conclude that ILP compared to aspiration alone, for recurrent benign predominantly cystic thyroid nodules, increases the remission rate from 18 to 68%. If long-term data confirm safety, the high remission rate, preservation of the solid nodule component reduction, and relief of pressure symptoms, ILP should be added to the therapy algorithm for this condition as a cost-effective alternative to PEI (7, 20). Acknowledgments Address all correspondence and requests for reprints to: Laszlo Hegedüs, MD, DMSci, Department of Endocrinology and Metabolism, Odense University Hospital, DK-5000 Odense C, Denmark. laszlo.hegedus@ouh.regionsyddanmark.dk. Disclosure Summary: The authors have nothing to disclose. L.H. is supported by an unrestricted research grant from the Novo Nordisk Foundation. References 1. Hegedüs L, Bonnema SJ, Bennedbæk FN. Management of simple nodular goiter: current status and future perspectives. Endocr Rev. 2003;24: Henrichsen TL, Reading CC, Charboneau JW, Donovan DJ, Sebo TJ, Hay ID. Cystic change in thyroid carcinoma: prevalence and estimated volume in 360 carcinomas. J Clin Ultrasound. 2010;38: Bellantone R, Lombardi CP, Raffaelli M, et al. Management of cystic or predominantly cystic thyroid nodules: the role of ultrasoundguided fine-needle aspiration biopsy. Thyroid. 2004;14: Bennedbæk FN, Karstrup S, Hegedüs L. Percutaneous ethanol injection therapy in the treatment of thyroid and parathyroid diseases. Eur J Endocrinol. 1997;136: Hegedüs L, Hansen JM, Karstrup S, Torp-Pedersen S, Juul N. Tetracycline for sclerosis of thyroid cysts. A randomized study. Arch Intern Med. 1998;148: Bennedbæk FN, Hegedüs L. Percutaneous ethanol injection therapy in benign solitary solid cold thyroid nodules: a randomized trial comparing one injection with three injections. Thyroid. 1999;9: Paschke R, Hegedus L, Alexander E, Valcavi R, Papini E, Gharib H. Thyroid nodule guidelines: agreement, disagreement and need for future research. Nat Rev Endocrinol. 2011;7: Døssing H, Bennedbæk FN, Hegedüs L. Effect of ultrasound-guided interstitial laser photocoagulation on benign solitary solid cold thyroid nodules a randomised study. Eur J Endocrinol. 2005;152: Døssing H, Bennedbæk FN, Hegedüs L. Effect of ultrasound-guided interstitial laser photocoagulation on benign solitary solid cold thyroid nodules: one versus three treatments. Thyroid. 2006;16:

5 doi: /jc jcem.endojournals.org E Døssing H, Bennedbæk FN, Hegedüs L. Long-term outcome following interstitial laser photocoagulation of benign cold thyroid nodules. Eur J Endocrinol. 2011;165: Døssing H, Bennedbæk FN, Hegedüs L. Beneficial effect of combined aspiration and interstitial laser therapy in patients with benign cystic thyroid nodules: a pilot study. Br J Radiol. 2006;79: Bennedbæk FN, Hegedüs L. Treatment of recurrent thyroid cysts with ethanol: a randomized double-blind controlled trial. J Clin Endocrinol Metab. 2003;88: Papini E, Bizzarri G, Pacella CM. Percutaneous laser ablation of benign and malignant thyroid nodules. Curr Opin Endocrinol Diabetes Obes. 2008;15: Døssing H, Bennedbæk FN, Bonnema SJ, Grupe P, Hegedüs L. Randomized prospective study comparing a single radioiodine dose and a single laser therapy session in autonomously functioning thyroid nodules. Eur J Endocrinol. 2007;157: Papini E, Guglielmi R, Bizzarri G, et al. Treatment of benign cold thyroid nodules: a randomized clinical trial of percutaneous laser ablation versus levothyroxine therapy or follow-up. Thyroid. 2007; 17: Valcavi R, Riganti F, Bertani A, Formisano D, Pacella CM. Percutaneous laser ablation of cold benign thyroid nodules: a 3-year follow-up study in 122 patients. Thyroid. 2010;20: Papini E, Bizzarri G, Bianchini A, et al. Percutaneous ultrasoundguided laser ablation is effective for treating selected nodal metastases in papillary thyroid cancer. J Clin Endocrinol Metab. 2013; 98:E92 E Hegedus L. Therapy: a new nonsurgical therapy option for benign thyroid nodules? Nat Rev Endocrinol. 2009;5: Sung JY, Kim YS, Choi H, Lee JH, Baek JH. Optimum first-line treatment technique for benign cystic thyroid nodules: ethanol ablation or radiofrequency ablation? AJR Am J Roentgenol. 2011; 196: Hegedüs L. Clinical practice. The thyroid nodule. N Engl J Med. 2004;351: Save the Date for Pediatric Endocrine Board Review (PEBR), September 24 25, 2013, Hyatt Regency New Orleans New Orleans, LA