First published online July 5, 2006
British Journal of Radiology (2006) 79, 943-947
© 2006 British Institute of Radiology
doi: 10.1259/bjr/40698061
Beneficial effect of combined aspiration and interstitial laser therapy in patients with benign cystic thyroid nodules: a pilot study
H Døssing, MD1,
F N Bennedbæk, MD, PhD2 and
L Hegedüs, MD, DSc3
1 Department of Oto-rhino-laryngology and Neck Surgery, Odense University Hospital, 2 Department of Endocrinology and Metabolism, Herlev University Hospital, 3 Department of Endocrinology and Metabolism, Odense University Hospital, Denmark
Correspondence: Helle Døssing, Department of Oto-rhino-laryngology and Neck Surgery, Odense University Hospital, DK- 5000 Odense C, Denmark. E-mail: h.doessing{at}dadlnet.dk
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Abstract
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The aim of this study was to evaluate the effect of combined cyst aspiration and ultrasound-guided interstitial laser photocoagulation (ILP) on recurrence rate and the volume of benign cystic thyroid nodules. 10 euthyroid outpatients with a solitary and cytologically benign partially cystic thyroid nodule causing local discomfort were assigned to cyst aspiration followed by ultrasound-guided ILP and followed for 12 months. The ILP was performed under continuous ultrasound-guidance and with an output power of 2.5–3.5 W. The volume of the nodules was assessed by means of ultrasound and determination of the amount of aspirated cyst fluid, thereby calculating the volume of the solid part. Follow-up included ultrasound and determination of thyroid function. Pressure and cosmetic complaints were evaluated on a visual analogue scale. The median initial volume of the cystic nodule decreased from 9.6 ml [6.8;15.5 (quartiles)] to 3.5 ml [2.7;9.0 (quartiles)] (p = 0.0001), and the median cyst volume from 3.0 ml [2.0;6.0 (quartiles)] to 0 ml [0;0.5 (quartiles)] (p = 0.0001) during follow-up. Recurrence of the cystic part was defined as a cyst volume > 1 ml. In eight of 10 patients there was no recurrence of the cystic part. Both pressure symptoms and cosmetic complaints were significantly reduced. The only side effect was mild pain or tenderness for a few days. Our study suggests that complete cyst aspiration and subsequent ultrasound-guided ILP of benign cystic thyroid nodules is a feasible and safe technique, resulting in a significant reduction in the volume of both the solid and the cystic component. A large-scale prospective randomized study is warranted.
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Introduction
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Benign nodular thyroid disease is very common in the adult population and the prevalence increases with age [1–4]. Approximately 85% of all thyroid nodules are non-functioning and, when evaluated by ultrasound, 15–25% of solitary thyroid nodules are cystic or predominantly cystic [1–4]. The incidence of thyroid cancer in cystic nodules is low and comparable with that of solid cold thyroid nodules [4]. Fine needle aspiration biopsy (FNAB) has been reported to be less efficacious for cystic nodules because of a greater frequency of acellular aspirates [5]. The use of ultrasound-guided FNAB from the solid part of the mixed cystic and solid nodule can reduce the number of insufficient biopsies, and improve the diagnostic accuracy [6, 7].
Simple aspiration of the cystic part may reduce the pressure-related symptoms, but the recurrence rate is up to 80%, depending on the number of previous aspirations and the cyst volume [8]. Percutaneous ethanol injection therapy (PEI) is effective in inducing necrosis and subsequent shrinkage in autonomously functioning thyroid nodules, as well as in cold nodules [9, 10]. The major limitation of PEI is the difficulty in predicting the diffusion of the ethanol, which can cause side effects related to extranodular seepage [9]. However, in cystic nodules PEI performs well with few side effects [11].
Recently, we and others introduced interstitial laser photocoagulation (ILP) for benign solitary solid cold thyroid nodules [12–16]. The procedure has been performed on an outpatient basis and is well tolerated. The nodule volume reduction and nodule related symptoms are comparable with that obtained following PEI therapy [9, 12, 13, 17], but side effects, especially pain, are less pronounced than during PEI therapy and no serious side effects have been reported [12, 13].The aim of this feasibility study was to evaluate the effect of combined cyst aspiration and ultrasound-guided ILP on the nodule volume and recurrence rate of the cystic part in benign mixed cystic and solid thyroid nodules.
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Patients and methods
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This prospective study included 10 consecutive patients (9 females and 1 male with a median age of 46.5 years, range 26–67 years) referred from their general practitioner due to a palpable thyroid nodule. All had cosmetic and/or pressure symptoms. All patients had a benign cold solitary cystic-solid thyroid nodule evaluated clinically, scintigraphically and by ultrasound-guided FNAB. Both specimens of the solid part as well as a centrifugate of the cyst fluid were evaluated by an experienced cytopathologist. Cytology was compatible with a cystic colloid goitre in all specimens. Furthermore, all had recurrence of the cystic part after the initial diagnostic aspiration. Clinically, there was no suspicion or family history of thyroid cancer. None had undergone prior radiation to the neck. All were euthyroid and had normal serum calcitonin levels. Blood tests included serum thyrotropin (TSH) (normal range, 0.3–4.0 mU ml–1) determined by DELFIA (Wallac, OY, Turku, Finland), serum total thyroxine (T4) (normal range, 65–135 mmol l–1) determined by radioimmunoassay (RIA) (Dianostic Products Corp., Los Angeles, CA) and serum total triiodothyronine (T3) (normal range, 1.00–2.10 mmol l–1) determined by RIA (Johnson & Johnson, Clinical Diagnostics Ltd., Amersham, UK). Free thyroxine and triiodothyronine (FT4 and FT3) indices were calculated multiplying serum T4 and T3 levels by the percentage of T3 resin uptake. Serum antithyroid peroxidase antibodies (anti-TPOAb) were determined by RIA DYNO test (Brahms diagnostica GMBH, Berlin, Germany; normal range <60 U ml–1). An indirect laryngoscopy was performed immediately before and 1 month after treatment by a specialist in otorhinolaryngology to evaluate motility of the vocal cords. ILP was carried out on an outpatient basis. At enrolment and at the 12 month evaluation, the patients were asked to rate pressure symptoms and cosmetic complaints on a visual 10 cm analogue scale (0–10 cm). Immediately after termination of the ILP-procedure, the patients were asked to rate the degree of pain/discomfort on a visual analogue scale. The patients were investigated 1 month, 3 months, 6 months and 12 months after the treatment. Initially, and during the follow up, cyst volume, volume of the solid part and total thyroid volume as well as serum thyroid hormones and serum TSH were investigated. Furthermore, anti-TPOAb were measured at the 12 month evaluation. The volume of the nodules was calculated on the basis of an ultrasonic scanning procedure using a 5.5 MHz static compound scanner (type 1846; B&K Medical, Gentofte, Denmark) [18]. Recurrence of the cystic part was defined as the presence of more than 1 ml (determined by ultrasound). The initial cyst volume was calculated by ultrasound and this result was compared with the aspirated volume.
Ultrasound examinations were performed using a Logiq 500 ultrasound scanner (GE Medical Systems, Milwaukee, WI) with a 12 MHz linear transducer (type 739L) mounted with a needle steering device for precise ultrasound-guided punctures. Under sterile conditions and guided by ultrasound, the laser fibre (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 anaesthesia with lidocaine (10 mg ml–1). Under sterile conditions and guided by ultrasound, the steering needle was positioned in the cystic part of the thyroid nodule. When the cystic part was completely aspirated, the steering needle was left in situ and the laser fibre was positioned in order to induce necrosis and destroy the cystic membrane and the solid part of the nodule. The entire procedure was performed under continuous ultrasound-guidance. The output power was between 2.5 W and 3.5 W dependent on the size of the solid part of the nodule. The laser power source was provided from a continuous-wave infrared (820 nm) diode (model 15; Diomed, Cambridge, UK). The vapour was clearly visible on ultrasound as an irregular hyperechogenic area enlarging over time, and the procedure was terminated when absence of flow signs in the treated areas evaluated by colour Doppler was seen. Typically two or three areas were treated (dependent on the size of the solid part and accessibility) before the procedure was terminated. The needle insertion and laser usage had a total duration of approximately 10 min, including interruptions with re-positioning of the fibre. The patients were instructed to give a sign before swallowing. The energy was turned off during swallowing and correct position of the laser fibre was assured by ultrasound before the treatment was resumed. Ultrasound measurements were performed by the same investigator (HD) with blinding towards the previous measurements.
The protocol was approved by the ethics committee of the county of Funen (journal no. 20030181). All patients provided signed informed consent before inclusion.
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Statistics
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Results for continuous data are given as medians and quartiles. Change in nodule volume was tested by means of a Wilcoxon signed ranks test.
Pressure symptoms and cosmetic complaints were rated on a 0–10 cm visual analogue scale before the 12 month evaluation and changes were evaluated by a Sign test.
Correlation between energy deposition and reduction in nodule volume at 12 months evaluation was performed by means of Spearman's rank correlation coefficient.
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Results
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The median duration of the nodule related symptoms was 6 months [3; 9 (quartiles)]. The median energy applied was 1390 J [895; 2022 (quartiles)] corresponding to a median energy of 254 J ml–1 initial post-aspirated nodule volume, i.e. per ml solid tissue. The duration of the treatment was 480 s [389; 746] (median and quartiles).
The median pre-treatment volume of the cystic nodules was 9.6 ml [6.8; 15.8 (quartiles)] and decreased significantly (p = 0.0003) to 3.5 ml [2.7; 6.2 (quartiles)] at 12 months. The overall median reduction was 57% [40; 72] (Figure 1
). The median pre-treatment cyst volume was 3.0 ml [2.0; 6.0 (quartiles)] and decreased significantly (p = 0.0001) to 0 ml [0; 0.5 (quartiles)] at 12 months (Figure 1). Recurrence was seen in only two patients during follow-up. In one patient, the cyst volume increased from 3 ml to 6 ml in defiance of needle aspiration during the observation period. She wished no further therapy. In the other patient the cystic part decreased from 4 ml to 1 ml without further therapy/aspirations.
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Figure 1. Total nodule volume of the mixed cystic-solid nodule, the cystic part and the post-aspirated nodule before and 1 month, 3 months, 6 months and 12 months after interstitial laser photocoagulation (ILP) (median and quartiles). There was a significant decrease in nodule volume from 0 to 3 months (p = 0.0003) and no significant change from 3 months to 12 months (p = 0.65).
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Initially, all the patients had cosmetic complaints and seven of the patients also had pressure symptoms. Five patients with pressure symptoms and seven patients with cosmetic complaints had complete relief of symptoms. According to the self-estimated ratings on a visual analogue scale, median pressure symptoms were reduced from 1.0 [1.0; 5.0 (quartiles)] to 0 [0; 0.5 (quartiles)] (p = 0.03) and cosmetic complaints from 3.5 [2.0; 5.0 (quartiles)] to 0 [0; 2.0 (quartiles)] (p = 0.004) during 12 months follow-up. In two patients ILP induced pain, which disappeared immediately when the energy was turned off. These two patients subsequently had moderate pain for 4 days. Both patients were treated with mild analgesics in this period. The other eight patients experienced only mild tenderness for one or 2 days and described this as equal to that experienced at the FNAB procedure. If offered, all but one consented to additional laser therapy. No serious side effects were recorded and all had normal post-therapy indirect laryngoscopy.
There was no significant correlation between the energy applied per ml nodule tissue and nodule volume reduction (r = 0.4; p = 0.2). Thyroid function remained unaltered throughout the study and TPOab remained negative in all (data not given).
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Discussion
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The vast majority of solid as well as mixed solid and cystic thyroid nodules grow over time [19]. A considerable number of these patients present with symptoms due to the nodule itself. Cystic thyroid nodules are a common cause of non-diagnostic rather than false-negative FNAB results, and recommendations for treatment should be based on cytological results or failure of cyst resolution [4, 5]. Simple aspiration may be of therapeutic value, but the efficacy varies considerably [1]. PEI sclerotherapy reduces recurrence rate of thyroid cysts relapsed after evacuation alone or after flushing with saline [11]. In the latter large scale, double-blind, randomized placebo-controlled study we found that 78% of the patients were cured after one PEI injection and the overall cure rate (one to three PEI injections) was 82% compared with an overall cure rate of 48% after saline injection [11]. The limitations and disadvantages of PEI therapy are related to the difficulty in predicting the diffusion of the ethanol. Side effects related to ethanol seepage outside the capsule may cause pronounced pain, or even more serious side effects such as paresis of the vocal cords or extraglandular fibrosis, which may impede subsequent surgery, in case of treatment failure [8, 9, 20]. However, in cystic nodules pain seems to be less pronounced and of shorter duration than described after injection in solid nodules [8, 9, 11].
In benign nodular thyroid disease, we and others have introduced ILP as an alternative to surgery for non-functioning solid nodules, in highly selected patients [12, 13, 15]. ILP is a minimally invasive interventional procedure of thermal ablation with the advantage of allowing the extent of tissue destruction to be controlled [21, 22]. The nodule volume reduction after ILP is comparable with that obtained following PEI, but ILP seems to have fewer side effects, especially less pain than that seen with PEI [9, 12–15, 17, 23].
In contrast to ethanol, the necrosis induced by ILP appears to be more regular and reproducible when using low power energy (2–5 W) [21, 22]. Under ultrasound-guidance, the laser fibre is clearly visualized as a hyperechoic spot (Figure 2) and during ILP, the area treated is clearly visualized as an echogenic area enlarging over time (Figure 3). This serves as a rough measure for the extent of the necrosis during the procedure [12–15, 21]. We recommend that termination of the treatment is preceded by colour Doppler evaluation to ensure the absence of flow signs in the treated area as an additional surrogate marker of complete necrosis. Therefore, the advantage of ILP is the great precision in inducing a well-defined area of tissue ablation with a reproducible pattern. ILP is effective in inducing necrosis and subsequent nodule shrinkage in solid cold thyroid nodules [12–15, 21]. In the present study we treated 10 patients with a solitary cystic thyroid nodule after aspiration of the cystic part. Resolution of the cystic part was achieved in eight of 10 patients (80%), which is much higher than that seen after aspiration alone or combined with flushing with saline [11]. As for the solid part of the nodule, an overall median nodule volume reduction of 57% was demonstrated and this was associated with relief of pressure symptoms and cosmetic complaints in all patients. The nodule volume reduction is comparable with or better than that obtained by one PEI therapy [8, 9]. Previously, we have demonstrated a mean reduction of 45% in solid thyroid nodules after one ILP treatment [12, 13]. The median energy given in that study was 254 J ml–1 of initial nodule tissue, which is equal to the energy given in one of our other studies [13]. However, the pre-treatment nodule volume of the solid part was smaller in the present study, which may explain the larger volume reduction. It is surprising that neither the present nor previous studies have reported a significant correlation between the energy given and nodule volume reduction [12, 13]. However, different biological characteristics such as the amount of colloid, the vascularization and pre-existing fibrosis of the nodule may possibly account for the optical properties of the thyroid nodule and thereby differences in and unpredictability of responsiveness. Thus, different morphological and degenerative changes in the nodule may favour the optical properties and may explain the better outcome in the present study. The only side effect was slight to moderate pain or tenderness; however, we consider these mild since nearly all patients would consent to additional treatments if offered. We now routinely offer pre-treatment mild analgesics.
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Figure 2. Longitudinal ultrasound scan of a post-aspirated mixed nodule before interstitial laser photocoagulation (ILP). Cursors indicate the outer margins of the nodule. Arrow illustrates the position of the fibre in the centre of the nodule just after the fluid has been aspirated. Small arrow illustrates the cyst wall.
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Figure 3. Longitudinal ultrasound scan of the nodule during treatment. Cursors indicate the outer margins of the nodule. The area above the arrow shows the irregular echogenic area, which enlarges over time during the treatment.
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It is recommended that a safety distance of at least 1 cm to contiguous structures such as the laryngeal nerve, the upper airways and the carotid arteries is maintained. Therapy should be performed in centres with expertise in ultrasound-guided interventional procedures in order to keep side effects to a minimum.
These preliminary data demonstrate that ultrasound-guided ILP after complete cyst aspiration is a feasible and safe technique. The technique seems to be a promising non-surgical alternative in patients with benign enlarging or recurrent cystic-solid thyroid nodules, but results need to be confirmed in randomized studies and further follow-up is needed to evaluate the long term efficacy.
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Acknowledgments
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This study was supported economically by: The Agnes and Knut Mørk Foundation, The Novo Nordisk Foundation, The A. P. Møller Relief Foundation, and The A. J. Andersen and Wife Foundation.
Received for publication January 31, 2006.
Revision received April 18, 2006.
Accepted for publication May 8, 2006.
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Abstract
Introduction
