Objective. To evaluate the efficacy and safety of percutaneous polidocanol injection (PPI) in treating cystic thyroid nodules. Materials and Methods. A total of 158 cystic or predominantly cystic thyroid nodules (>80% cystic component) in 143 patients were evaluated. 114 patients with compressive symptoms or aesthetic complaints were offered PPI. 44 individuals without compressive symptoms and aesthetic complaints who were only followed up clinically were used as the control group. The efficacy and safety of PPI were evaluated for 1 month, 3 months, 6 months, 9 months, and 12 months of follow-up. Results. In the PPI group, the mean baseline volume of 15.6±18.9 cm3 reduced at the 1-month follow-up to 5.1±5.6 cm3 (p<0.001) and 0.6±0.9 (p<0.001), and nodules shrunk according to the time after PPI (p<0.001). A complete response (if ≥70% decrease) to PPI at the 12-month follow-up occurred in 100% of the cystic or predominant cystic nodules. None of the nodules recurred at the 12-month follow-up after PPI. The side effects were mild. Twenty patients (17.5%) developed mild localized pain, and fourteen cases (12.3%) experienced mild or moderate fever after PPI. Conclusions. PPI is a safe and effective alternative to treat benign cystic or predominant cystic thyroid nodules.
Wenzhou Science and Technology BureauY201500401. Introduction
Thyroid nodules are characterized by excessive structural growth, functional transformation, and/or cystic degeneration of one or several areas within the gland [1]. According to various studies, 15–30% of thyroid nodules are cystic or predominantly cystic [2, 3]. After simple fine-needle aspiration, most cystic lesions (around 80%) refill and enlarge over time [4]. Surgery is a long-established therapeutic option for benign thyroid nodules. However, the cost of thyroid surgery, risk of temporary or permanent complications, and impact on quality of life remain relevant concerns. Ethanol ablation (EA) is an effective and safe treatment technique [5]. However, in a randomized study, percutaneous ethanol injection (PEI) achieved remission in 68% of cystic thyroid nodules after one treatment injection [4]. Ethanol sclerotherapy is also associated with some complications. Mild transient pain or a burning sensation at the site of injection is the most commonly seen following ethanol sclerotherapy and is a result of leakage of ethanol into the subcutaneous tissue [4, 6]. Other uncommon complications include hematoma, dyspnea, and vocal cord paralysis [7, 8]. More importantly, it is difficult to obtain the 99% ethanol in China. Therefore, there is a need for novel sclerosants. Polidocanol injection is well known as a novel foam sclerosant that is currently administered by injection mostly for the treatment of hemangiomas [9], haemorrhoidal disease [10], symptomatic hepatic cysts [11], gastric varices [12], and reticular veins of the lower limbs [13]. The aim of the present study was to prospectively determine the efficacy and safety of polidocanol injection for the treatment of benign cystic or predominant cystic thyroid nodules.
2. Materials and Methods
From October 2013 to April 2015, a total of 117 cystic (>90% cystic component) and 41 predominantly cystic thyroid nodules (>80% cystic component) in 143 patients (128 patients had single nodule, and 15 patients had two cystic or predominantly cystic nodules) were evaluated with fine-needle aspiration cytology (FNAC), using 21 G hypodermic needles at the outpatient clinic of The First Affiliated Hospital of Wenzhou Medical University. And complete fluid aspiration was performed at this time. Benign cytological results were from two separate US-guided fine-needle aspirations to exclude malignancy. 114 consecutive patients with compressive symptoms or aesthetic complaints were offered polidocanol treatment. 44 individuals without compressive symptoms and aesthetic complaints who were only followed clinically were used as the control group. This prospective study was conducted over a period of one year.
US examination was performed in all patients before treatment and at the time of the 1, 3, 6, 9, and 12 months of follow-up examinations. The three orthogonal diameters of each nodule that were measured were the largest diameter and two mutually perpendicular diameters. The volume of each nodule was calculated using the equation volume=πabc/6, where a is the largest diameter and b and c are the other mutually perpendicular diameters. Upon US examination, the changes in the volume of the nodules were evaluated.
Before and after PPI treatment, the patients were asked to rate pressure symptom score on a visual analog scale (0–10 cm) and cosmetic grade ((1) no palpable mass, (2) a palpable mass but no cosmetic problem, (3) cosmetic problem on swallowing only, and (4) readily detected cosmetic problem) [14].
To assess safety, any possible complications both during and immediately after the procedure were evaluated. Major and minor complications were defined by the definitions of the Society of Interventional Radiology [15]. Procedure-related pain was graded into four categories (grade 0, no pain or mild pain similar to pain during lidocaine injection; grade 1, pain greater than lidocaine injection, but not needing medication; grade 2, pain needing medication; grade 3, PPI procedure incompletely terminated due to severe pain) [14].
According to the decrease in nodular volume, polidocanol results were categorized as incomplete response (if <70% decrease) or complete response (if ≥70% decrease) [16].
The procedures were performed in the outpatient clinic. Patients were placed in a supine position with mild neck extension. An 18-gauge needle was inserted into the cystic portion of the thyroid nodule under ultrasound guidance without local anesthesia. The fluid was first completely aspirated. The syringe tube was then replaced with another one containing polidocanol injection while keeping the puncture needle in place. The amount of polidocanol injected was about 25–33% of the amount of fluid aspirated. Then, we extracted and flushed the injection for 5 times to assure the uniform distribution of the injection and the polidocanol was left in the cysts (Figure 1).
Ultrasonographic images of a 23-year-old woman before, during, and after treatment: (a) a cystic thyroid nodule of ultrasonographic images before PPI treatment; (b) during PPI treatment; (c) 12 months after PPI treatment; the nodule decreased significantly (arrow). PPI: percutaneous polidocanol injection.
This study was approved by the Ethics Committee of The First Affiliated Hospital of Wenzhou Medical University. All study participants provided written informed consent before the experiments. The written informed consent was provided by each eligible patient, and the study conformed to the Declaration of Helsinki.
3. Statistical Analysis
The comparison of parametric quantitative variables between both groups was analyzed with Student’s t-test and nonparametric variables with the Mann–Whitney test. Qualitative variables were evaluated with the chi-square test. The comparison of volumes at different periods was conducted with the Friedman test, confirmed with nonparametric multiple comparison for dependent data. The same comparison in the control group was conducted with the paired Wilcoxon test. We applied the likelihood ratio to compare complete or incomplete response rates after polidocanol treatment using the chi-square test. Multivariate analysis was performed with the Statistical Package for Social Sciences (SPSS), version 19.0. We used a confidence interval of 95% and a significance level of 5%.
4. Results
The clinical data for 114 consecutive patients with polidocanol treatment and 44 individuals in the control group are given in Table 1. At baseline, the volume of the nodules in the polidocanol treatment group ranged from 2.5 to 138.7 cm3, with an average of 15.6±18.9 cm3. In the control group, the initial volume of the nodules ranged from 0.9 to 14.2 cm3 (mean 2.3±3.0 cm3). After a follow-up of 12 months, the volumes in the control group ranged from 0.4 to 16.4 cm3 (mean 2.8±3.5 cm3, p=0.501).
Clinical characteristics of patients in the PPI and control groups.
At 1-month follow-up, the volume of the nodules in PPI group ranged from 0.2 to 31.30 cm3, with an average of 5.1±5.6 cm3. At 3 months, 6 months, and 9 months of follow-up, the cyst nodules showed significant reduction in the volume. The mean volumes of nodules at the 3 months, 6 months, and 9 months of follow-up were 2.0±3.8 cm3, 0.7±1.0 cm3, and 0.7±0.9 cm3, respectively. At 12-month follow-up, the nodules ranged in volume from 0.01 to 4.9 cm3, with an average of 0.6±0.9 cm3. Compared with the baseline volume, the reduction after PPI treatment showed a significant difference (p<0.01, Figure 2).
Volumes at baseline and the time of follow-up in the PPI group; volumes at baseline and the time of follow-up in the control group. PPI: percutaneous polidocanol injection.
Compared with the volume at 1-month follow-up, the reduction at 12-month follow-up was also significantly different (p<0.01, Figure 2). Compared with the outcomes between both groups, we observed that the nodules in the PPI group showed a significantly larger reduction in volume (p<0.001, Figure 2).
Compared with baseline, a reduction at 1-month follow-up was 65.11±23.01% (p<0.001, Table 2). Compared with the volume at 1-month follow-up, the reduction at 12-month follow-up showed a significant difference (p<0.001, Table 2). The therapeutic success rate to PPI at 1-month follow-up occurred in 36.8% of the cystic or predominant cystic nodules. At 3-month follow-up, the therapeutic success rate to PPI was observed in 89.5% of the nodules, 98.2% of the nodules at 6-month follow-up, and 100% of the nodules at 12-month follow-up (p for comparison between all the follow‒ups<0.001). Mean symptom score and cosmetic grade also significantly vanished in the vast majority at last follow-up of PPI group (p<0.001, Table 2).
Efficacy of PPI in cystic thyroid nodules at follow-up.
Baseline
1 month
3 months
6 months
12 months
p
Size reduction (%)
—
65.11±23.01
85.87±14.45
94.75±5.76
95.58±4.18
<0.001
Success rate, n (%)
—
42/114 (36.8)
102/114 (89.5)
112/114 (98.2)
114/114 (100)
<0.001
Symptom score
4.71±1.62
2.34±0.96
1.12±0.83
0.21±0.40
0.21±0.40
<0.001
Cosmetic grade
3.49±0.50
2.05±0.64
1.65±0.53
1.37±0.50
1.21±0.41
<0.001
PPI: percutaneous polidocanol injection.
A comparison of the results between baseline and post-PPI showed no statistical difference in TSH (p=0.579) or free T4 (p=0.621) levels.
Twenty of the 114 (17.5%) patients after PPI treatment reported mild localized pain that lingered for 1 to 3 days. Fourteen cases of the 114 (12.3%) patients experienced mild or moderate fever after polidocanol injection. The fever lingered for 1–4 days that required no treatment or antipyretic drug. None suffered the major complications in this study.
5. Discussion
Simple aspiration is the treatment of choice for diagnostic and therapeutic purposes in symptomatic patients with cystic or predominant cystic thyroid nodules. However, the recurrence rate is up to 80% [17], even after repeated aspirations. Success rate of PEI, defined as near disappearance or marked size reduction (>50%), has been reported to vary from 72% to 95% [4, 8, 16]. PEI remains the first line treatment for pure thyroid cysts or predominantly cystic (cystic components comprising>80%) benign nodules [18, 19]. However, a prospective randomized double-blind study showed that the cure was obtained in 64% of patients after one treatment of PEI sclerotherapy only and the other patients needed one more treatment session [4]. 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 [7]. Radiofrequency (RAF) is scarcely employed in the management of cystic thyroid lesions. Although both ethanol ablation and RFA are effective and safe treatment techniques, ethanol ablation is a less expensive and simpler procedure than RFA [20].
It is difficult to obtain the 99% ethanol used as a sclerosant in China because the absolute ethanol production has been disrupted for four years, and hospital-made absolute ethanol cannot obtain the registered document of approval. Polidocanol (Polidocanol®) is an effective sclerosant consisting of 95% hydroxypolyethoxydodecane and 5% ethyl alcohol. The Food and Drug Administration (FDA) has approved polidocanol as a medicinal sclerosant in the United States, as it has its equivalents in European countries.
Although there are many studies in other areas, few studies have examined polidocanol as a sclerosant for cystic or predominant cystic thyroid nodules. In our present study, the rate of volume reduction of the nodules was 95.58% 12 months after PPI. Moreover, we achieved a 100% therapeutic success (size reduction>70%) in 114 patients and none of the nodules recurred at 12-month follow-up. The observed success rate was better than those reported previously PEI [14, 21]. And symptom scores and cosmetic scores vanished in the vast majority. The mechanism of treating cyst is probably destroying endothelial cells of capsule wall which causes aseptic inflammation; thus endothelial tissue atrophies and cyst cavity adhere and occlude [22]. A rabbit model histopathologic evaluation results revealed that inflammation and fibrosis were significantly increased. This finding shows that polidocanol can be effectively used to treat thyroid nodules by means of fibrosis [23]. Meanwhile, it has anesthetic effects, no need for intracystic anesthesia or sedation for the patients [24]. The primary clinical application of polidocanol is its endovascular use for sclerosing varicose veins, and, therefore, it is a safer agent for using without reaspiration. It can be left in the cyst cavity to achieve a complete adhesion with only a one-step application. So its procedure was easier than PEI.
In our experience, mild pain was only seen in 17.5% of patients and mild or moderate fever was seen in 12.3% patients treated with PPI. There were no serious side effects related to ethanol seepage outside the capsule.
The present study had some limitations. We did not compare PPI treatment with a control group treated with ethanol because we could not obtain absolute ethanol. Secondly, the patients were followed up only for one year. Further studies with larger patient samples are needed to confirm these findings.
The findings of this study indicate that PPI is a safe, effective, and rapid treatment that can be performed on an outpatient basis. The cost of PPI treatment for benign cystic or predominant cystic thyroid nodule is 600 RMB, and the cost of PEI treatment was 260 RMB. Although PPI has a higher cost than PEI, it is still inexpensive. In short, it may be an effective alternative to ethanol injection.
Conflicts of Interest
The authors have declared that no conflict of interest exists.
Authors’ Contributions
Xiaohua Gong, Qi Zhou, and Fang Wang contributed equally to this work.
Acknowledgments
This study was funded by the Wenzhou Science and Technology Bureau (Y20150040). The authors would like to acknowledge their colleagues in Endocrinology Department and Pathology Department of The First Affiliated Hospital of Wenzhou Medical University for the assistance in the present study.
HegedüsL.BonnemaS. J.BennedbaekF. N.Management of simple nodular goiter: current status and future perspectives20032411021321258881210.1210/er.2002-00162-s2.0-0037323540McHenryC. R.SlusarczykS. J.KhiyamiA.Recommendations for management of cystic thyroid disease19991266116711721059820310.1067/msy.2099.1014232-s2.0-0032732446MazzaferriE. L.Management of a solitary thyroid nodule19933288553565842662310.1056/NEJM1993022532808072-s2.0-0027465843BennedbækF. N.HegedüsL.Treatment of recurrent thyroid cysts with ethanol: a randomized double-blind controlled trial20038812577357771467116710.1210/jc.2003-0310002-s2.0-0346732366SungJ. Y.BaekJ. H.KimK. S.LeeD.YooH.KimJ. K.ParkS. H.Single-session treatment of benign cystic thyroid nodules with ethanol versus radiofrequency ablation: a prospective randomized study201326912933002361663010.1148/radiol.131221342-s2.0-84884683275PerezC. L.FigheraT. M.MiasakiF.Mesa JuniorC. O.Paz FilhoG. J.GrafH.CarvalhoG. A.Evaluation of percutaneous ethanol injections in benign thyroid nodules20145899129172562704610.1590/0004-27300000034442-s2.0-84921959809BennedbækF. N.KarstrupS.HegedüsL.Percutaneous ethanol injection therapy in the treatment of thyroid and parathyroid diseases19971363240250910054510.1530/eje.0.1360240JayeshS. R.MehtaP.CherianM. P.IlayarajaV.GuptaP.VenkateshK.Efficacy and safety of USG-guided ethanol sclerotherapy in cystic thyroid nodules20091931992021988108410.4103/0971-3026.548792-s2.0-68849107794GroverC.KhuranaA.BhattacharyaS. N.Sclerotherapy for the treatment of infantile hemangiomas2012532012032311251910.4103/0974-2077.101383MoserK. H.MoschC.WalgenbachM.BussenD. G.KirschJ.JoosA. K.GliemP.SauerlandS.Efficacy and safety of sclerotherapy with polidocanol foam in comparison with fluid sclerosant in the treatment of first-grade haemorrhoidal disease: a randomised, controlled, single-blind, multicentre trial20132810143914472377509910.1007/s00384-013-1729-22-s2.0-84884989755SpârchezZ.RaduP.ZaharieF.Al HajjarN.SparchezM.Percutaneous treatment of symptomatic non-parasitic hepatic cysts. Initial experience with single-session sclerotherapy with polidocanol201416322222825110763ClementsW.CavanaghK.AliF.KavnoudiasH.KempW.RobertsS.LyonS.Variant treatment for gastric varices with polidocanol foam using balloon-occluded retrograde transvenous obliteration: a pilot study20125665996052321057810.1111/j.1754-9485.2012.02453.x2-s2.0-84870591231BertanhaM.SobreiraM.Pinheiro Lucio FilhoC.de Oliveira MariubaJ.Farres PimentaR.JaldinR.MorozA.MouraR.RolloH.YoshidaW.Polidocanol versus hypertonic glucose for sclerotherapy treatment of reticular veins of the lower limbs: study protocol for a randomized controlled trial20141514972552716510.1186/1745-6215-15-4972-s2.0-84925121174KimY. J.BaekJ. H.HaE. J.LimH. K.LeeJ. H.SungJ. Y.KimJ. K.KimT. Y.KimW. B.ShongY. K.Cystic versus predominantly cystic thyroid nodules: efficacy of ethanol ablation and analysis of related factors2012227157315782243792010.1007/s00330-012-2406-52-s2.0-84864693704SacksD.TEM. C.CardellaJ. F.LewisC. A.Society of Interventional Radiology clinical practice guidelines200314919920210.1097/01.RVI.0000094584.83406.3e2-s2.0-3242877827FerreiraM. C.PiaiaC.CadoreA. C.Percutaneous ethanol injection versus conservative treatment for benign cystic and mixed thyroid nodules20166032112162691062210.1590/2359-39970000001202-s2.0-84989261696BennedbækF. N.NielsenL. K.HegedüsL.Effect of percutaneous ethanol injection therapy versus suppressive doses of L-thyroxine on benign solitary solid cold thyroid nodules: a randomized trial1998833830835950673610.1210/jcem.83.3.4673GuglielmiR.PacellaC. M.BianchiniA.BizzarriG.RinaldiR.GrazianoF. M.PetrucciL.ToscanoV.PalmaE.PoggiM.PapiniE.Percutaneous ethanol injection treatment in benign thyroid lesions: role and efficacy20041421251311506862710.1089/1050725043228803642-s2.0-12144290570GharibH.PapiniE.PaschkeR.DuickD. S.ValcaviR.HegedüsL.VittiP.AACE/AME/ETA Task Force on Thyroid NodulesAmerican Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European thyroid association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules201016Supplement 11432049793810.4158/10024.GL2-s2.0-77957312140SungJ. Y.KimY. S.ChoiH.LeeJ. H.BaekJ. H.Optimum first-line treatment technique for benign cystic thyroid nodules: ethanol ablation or radiofrequency ablation?2011196221021410.2214/AJR.10.51722-s2.0-79251525185KimJ. H.LeeH. K.LeeJ. H.AhnI. M.ChoiC. G.Efficacy of sonographically guided percutaneous ethanol injection for treatment of thyroid cysts versus solid thyroid nodules20031806172317261276095010.2214/ajr.180.6.1801723JieX.GengX.Curative effect of lauromacrogol and absolute ethyl alcohol injection guided by ultrasound on simplex hepatic cyst2014283697700IdizU. O.AysanE.CanI.BuyukpinarbasiliN.YardimciE. Y.BektasogluH.The effects of lauromacrogol on thyroid tissue in rabbits. Is this a safe option for the treatment of nodular thyroid disease?20168719219727179294YongucT.SenV.AydogduO.BozkurtI. H.YarimogluS.PolatS.The comparison of percutaneous ethanol and polidocanol sclerotherapy in the management of simple renal cysts20154746036072577881810.1007/s11255-015-0953-92-s2.0-84939984191