Percutaneous Laser Ablation of Cold Benign Thyroid Nodules: A 3-Year Follow-Up Study in 122 Patients

Abstract

Background:

Percutaneous laser ablation (PLA) is a proposed therapeutic procedure for the management of benign thyroid nodules. However, long-term results are unknown. The aim of this study was to evaluate retrospectively the safety and effects of PLA treatment in patients with benign nonfunctioning thyroid nodules in a 3-year follow-up.

Methods:

One hundred twenty-two patients (95 women and 27 men; age 52.2 ± 12.3 years) with benign cold thyroid solitary nodules or a dominant nodule within a normo-functioning multinodular goiter (volume range: 2.6–86.4 mL) underwent thermal Nd:YAG laser ablation of thyroid nodular tissue by 1–4 optical fibers positioned into the tissue by 21-gauge needles under ultrasound real-time assistance. The setting was an interventional suite and outpatient endocrine clinics in a community hospital in Italy. Nodule volume, ablation volume, side effects, serum thyroid-stimulating hormone (TSH), free triiodothyronine, free thyroxine (fT4), thyroglobulin (Tg), anti-Tg, anti-thyroperoxidase antibodies, symptoms, and cosmetic signs were recorded.

Results:

Data are mean ± standard deviation. Energy delivered was 8522 ± 5365 J with an output power of 3.1 ± 0.5 W. Three years after PLA, nodule volume decreased from 23.1 ± 21.3 to 12.5 ± 18.8 mL (−47.8% ± 33.1% of initial volume, p ≤ 0.001). At day 1, TSH and fT4 values significantly changed (time 0 vs. day 1: TSH = 1.16 ± 1.06 vs. 0.62 ± 0.81 μU/mL, p ≤ 0.001; fT4 = 11.68 ± 1.88 vs. 13.20 ± 3.32 pg/mL, p ≤ 0.01) and normalized within 1 month. No change in free triiodothyronine, thyroperoxidase antibodies, and Tg antibodies values was observed. Symptoms improved in 89 patients (73.0%), were unchanged in 28 (22.9%), and worsened in 5 (4.1%). Cosmetic signs improved in 87 patients (71.3%), were unchanged in 29 (23.8%), and worsened in 6 (4.9%). In 11 patients (9%), nodules regrew above baseline. Two patients (1.6%) experienced delayed (12–24 hours) laryngeal dysfunction with vocal cord motility recovery after 6–10 weeks. Two patients (1.6%) became hypothyroid and two patients (1.6%) hyperthyroid after PLA.

Conclusions:

After 3 years, the PLA technique achieved shrinkage of about 50% of the initial volume in a wide size range of benign cold thyroid nodules, with an improvement in local symptoms and signs. Side effects and failures were few although not negligible. PLA may be a new option for the management of benign cold thyroid nodules. Long-term controlled studies are required to establish the eligibility of patients for routine PLA.

Introduction

P resent guidelines offer patients with benign thyroid nodular disease either no treatment or partial/total thyroid surgery, depending on nodule size, growth, or symptoms (1,2). Nonsurgical therapy options, including ultrasound (US)-guided procedures, are presently under investigation (3). US-guided percutaneous ethanol injection may be the treatment of choice for cystic nodules (1,2,4) but is no longer recommended for solid nodules (1,2,5,6). High-intensity focused US was successfully investigated in ewes (7,8), but there are no data available in humans. Recently, radiofrequency (RF) thermal ablation has been proposed for the thyroid gland (9 –15). Percutaneous laser ablation (PLA) was the first thermal ablation technique introduced by Pacella et al. (16). Subsequently, several articles on PLA effects in cold (17,18), cystic (19), and hot thyroid nodules (18 –25) have been published, including controlled trials (26 –29), suggesting effectiveness and safety of this new technique. However, the number of patients studied so far is limited, follow-up data are restricted to 1 year, and long-term outcome of PLA is still unclear. We retrospectively studied a large population of patients treated with PLA for benign solid cold thyroid nodules of different sizes, with a 3-year follow-up.

Materials and Methods

Patients

The study design was retrospective and was approved by the institutional review committee of Arcispedale Santa Maria Nuova, Reggio Emilia, Italy. Files of 302 patients treated with PLA from January 2004 to December 2006 at our institution were reviewed. Patients were referred to our Thyroid Center Disease by their physicians for the PLA procedure with compressive symptoms: pressure symptoms, throat constraint, and/or swallowing difficulty (n = 65, 21.5%) or esthetic complaints (n = 54, 17.9%), or both (n = 183, 60.6%). The patients had refused surgery (n = 228, 75.5%) or had poor surgical indications because of previous thyroid surgery, age, or cardiovascular risk (n = 74, 24.5%). Among the whole group of 302 patients treated, we selected patients with the following inclusion criteria: both sexes; single nodule or a dominant, well-circumscribed nodule within a multinodular goiter; solid nodule or mixed nodule with a fluid component <20% of total volume; any size of the nodule between 2.5 and 90 mL, that is, the greater diameter ranging 1.5–7.0 cm; cold nodule on 99mTc scinti scan; normal thyroid-stimulating hormone (TSH) levels (0.35–4.5 μU/mL); normal free thyroxine (fT4) and free triiodothyronine (fT3) levels (8.0–18 and 2.3–4.2 pg/mL, respectively); anti-TSH-receptor antibodies (TRAb) level negative (<10 U/L); benign cytology (colloid and sheets of follicular cells without atypia, class 2 (1) at least two times on two to three nodule areas at each fine-needle aspirate [FNA]), the second cytology performed <6 months before PLA; normal calcitonin levels (<10 pg/mL); absence of US features suggesting malignancy (30,31); absence of familiar history of thyroid carcinoma of any histologic type; no history of previous radiation neck therapy; normal platelet count and blood coagulation tests; no repeat PLA sessions; 3-year follow-up.

Entry criteria were satisfied by 122 patients (95 women (77.9%); 27 men (22.1%); mean ± standard deviation [SD] age 52.2 ± 12.3; median 52.0; range 20–83 years) with cold thyroid solitary nodules (n = 43, 35.2%) or a dominant nodule within a normal-functioning multinodular goiter (n = 79, 64.8%). The study was carried out in accordance with the Helsinki Declaration. All patients gave their written informed consent for PLA procedure.

Preliminary assessment

The US features, FNA cytology, laboratory tests, 99mTc pertechnetate scinti scan, and clinical symptoms were assessed in all patients. US studies were performed with commercially available systems (Technos MPX; Mylab70XVG, Esaote, Italy), equipped with linear transducers operating at 7.5–18 MHz in the B-mode, and at 4.5–7.1 MHz for color Doppler. Nodules were measured in the three largest perpendicular diameters in thickness, width, and length. The 3 diameters (cm) were multiplied by 0.525 according to the ellipsoid formula. Volume was the mean of three consecutive measurements on cross-sectional images. The intra- and interobserver coefficient of variation of measurements were 7% and 9%, respectively. Indirect laryngoscopy was performed in all patients. The laboratory tests included TSH, fT3, fT4, anti-thyroperoxidase antibodies (TPOAb), anti-thyroglobulin antibodies (TgAb), TRAb, Tg, complete blood count, and blood coagulation tests. Patients on antiplatelet treatment or anticoagulant treatment withdrew therapy 72 and 48 hours before PLA procedure, respectively.

Procedure

PLA was performed as an outpatient procedure carried out in an interventional suite. Patients were fasting. The patient was placed on an operation bed in the supine position with hyperextended neck, and a venous catheter was inserted in a forearm vein. A multiparametric monitor was connected to the patient showing continuous electrocardiogram, pO2, blood pressure, and breath rate. Light conscious sedation was obtained with intravenous (i.v.) diazepam (2–10 mg) or i.v. midazolam (2–5 mg) in fractionated boli. Local anesthesia with 2% lidocaine subcutaneous subcapsular infiltration (2–5 mL) was performed under US assistance with thin (G27) needles. We used the ablation flat tip technique, proposed by Pacella et al. (16,18). Three-hundred-micrometer plane-cut optic fibers were inserted through the sheath of 21G Chiba needles, exposing the nude fiber in direct contact with thyroid tissue for a length of 5 mm. Optic fibers were connected with the laser source, a continuous-wave Nd-YAG laser operating at 1.064 μm with an optical beam-splitting device (DEKA; M.E.L.A., Florence, Italy). One to four needles was placed manually along the longitudinal, cranio-caudal, and major nodule axis, at a distance of 10 mm each, fitting at best to the anatomy and size of nodules (volume ≤15 mL, 1–2 fibers; volume >15 mL, 3–4 fibers). The procedure was started with the deposition of an initial energy of 1200–1800 J × fiber (volume ≤15 mL, 1200 J; volume >15 mL, 1800 J) in the caudal part of the nodule, 10 mm from the lower margin. By upward needle/fiber pull-backs of 10 mm, additional laser energies were administered until a distance of 5 mm from the cranial portion of the nodule was reached. Total illumination time (minutes) was automatically recorded by the laser equipment. Figure 1 shows images of the procedure and US follow-up. Immediately after PLA procedure, all patients received methyl-prednisolone 20 mg i.v. bolus. Patients were then brought in the recovery room, received ketoprofene 100 mg or paracetamol 1000 mg infusion, and were kept under observation for at least 2 hours. The day after, PLA procedure patients were started on oral prednisone 25 mg for 3 days, 12.5 mg for 3 days, and 5 mg for 4 days. Oral proton pump inhibitors were administered (lansoprazole 30 mg) for 10 days. Intraoperative, major, and minor complications, side effects, and long-term complications of treatment were described using the reporting standards of the Society of Interventional Radiology (32,33). Intraoperative complications and side effects not included in Society of Interventional Radiology guidelines were classified using the same criteria.

FIG. 1.

Percutaneous laser ablation (PLA) procedure of a right lobe nodule with three optic fibers. (A) Laser ablation: the operator positions himself or herself close to the patient's head (bottom), while an assistant holds a linear ultrasound (US) probe (top). Twenty-one-gauge Chiba needles with optic fibers are fit along the longitudinal, cranio-caudal, and nodule axis. The assistant will show real-time US images on axial and sagittal scans throughout the procedure. (B) Transverse US scan of the right thyroid nodule before ablation. Volume of the nodule was 22.7 mL. (C) Longitudinal US scans showing laser activity. Color Doppler images show laser firing. (D) Transverse US scan of the right thyroid nodule showing coagulation zone, a clearly defined hypoechoic, nonvascular tissue. Marks of the three fibers are clearly seen (arrows). (E) Transverse US scan of the right thyroid nodule 3 years after PLA. A hyperechoic mark corresponds to a fibrotic reaction. Volume was 7.8 mL, with a 65.6% reduction of initial mass.

Follow-up evaluation

US features, volume (mL), coagulation zone evaluated as the avascular, hypoechoic area (mL), laboratory tests, side effects, compressive symptoms, and cosmetic sign were recorded at days 1 and 7, and at months 6, 12, 24, and 36. Indirect laryngoscopy was performed at day 1 and year 3. Symptoms were defined as follows: score 0 = asymptomatic; score 1 = mild pressure complaint; score 2 = neck constraint; score 3 = neck constraint plus swallowing difficulty. Cosmetic signs were defined as follows: score 0 = nodule not visible; score 1 = nodule visible with hyperextended neck; score 2 = nodule visible at a distance ≤ 1 meter without extending neck; score 3 = nodule visible at a distance > 1 m. Improvement or worsening of symptoms and signs was defined as the change to upper or lower scores, respectively. TSH, fT3, fT4, Tg, TgAb, TPOAb, and TRAb were measured in the same laboratory by commercial kits.

Statistical analysis

Values for quantitative variables are expressed as the mean ± SD, median, and range. Values for qualitative variables are expressed as a percentage. The Spearman's rho coefficient was used to evaluate the level of correlation between initial volume and total energy administered. The Wilcoxon test was used to check if the absolute change in volume between two consecutive periods were statistically significant. p-Values < 0.05 were considered significant. Statistical analysis was performed using SPSS, version 17.0 (SPSS, Chicago, IL).

Results

The number of optic fibers placed was 2.4 ± 0.6 (median 2; range 1–4), total energy delivered was 8522 ± 5365 J (median 7000 J; range 1200–32,000 J), and the output power was 3.1 ± 0.5 W (median 3 W; range 2–4 W). Laser illumination time was 19.4 ± 8.4 minutes (median 19 minutes; range 10.0–40.0 minutes), and energy administered was 484 ± 365 J/mL of nodular tissue (median 474 J/mL; range 340–1154 J/mL). There was a correlation between initial volume and total J administered (r = 0.743; p ≤ 0.001). Coagulation zone, nodule change in size, and laboratory data are shown in Table 1. Nodule volume increased significantly at day 1 (p ≤ 0.001 vs. initial) and 1 week (p ≤ 0.001 vs. initial) after PLA procedure. Nodule volume decreased significantly versus initial (p ≤ 0.01) 1 month after PLA, and dropped after 6 months and 1, 2, and 3 years (p ≤ 0.001 vs. initial). After 3 years, a tendency to a mean volume increase was observed, although it was not significant versus 6 months, 1 year, and 2 years (p > 0.05.). Eleven (9.0%) out 122 patients followed-up at 3 years showed an increase in nodule volume above initial values. Repeat cytology was colloid and hyperplastic in the 11 patients with nodule recurrence. US structure revealed compact or spongiform architecture in 8 and 3 patients, respectively (Table 2). According to initial nodule volume, the patient population was stratified into quartiles. Thirty patients had small class 1 nodules (volume 2.6–8.2 mL; mean volume 5.1 mL), 31 patients had medium to small class 2 nodules (8.3–15.2 mL; mean 11.5 mL), 31 patients had medium to large class 3 nodules (15.3–29.4 mL; mean 21.1 mL), and 30 patients had large class 4 nodules (29.5–86.4 mL; mean 54.6 mL). Figure 2 shows mean percentage of volume changes in the four classes according to initial volume.

FIG. 2.

Mean percentage of nodule volume changes in 122 patients treated with PLA for benign thyroid nodule. At each time during the 3-year follow-up, columns indicate quartiles according to initial nodule volume (time 0). First quartile, 30 patients with small nodules (mean volume = 5.1 mL); second quartile, 31 patients with medium-small nodules (mean = 11.5 mL); third quartile, 31 patients with medium-large nodules (mean = 21.1 mL); fourth quartile, 30 patients with large nodules (mean = 54.6 mL).

Table 1.

Nodule Volume and Laboratory Tests in 122 Patients Treated with Percutaneous Laser Ablation for Benign Thyroid Nodule During the 3-Year Follow-Up

	Time 0	1 day	1 week	1 month	6 months	1 year	2 years	3 years
No. of patients	122	122	118	116	117	120	116	122
Volume (mL)
Mean ± SD	23.1 ± 21.3	24.7 ± 21.9	24.0 ± 22.3	20.5 ± 19.8	12.8 ± 15.1	11.7 ± 14.9	11.3 ± 15.7	12.5 ± 18.8
Median	15.2	17.6	16.7	13.6	7.5	6.7	6.3	7.0
Range	2.6–86.4	3.2–94.9	2.9–92.5	2.3–85.3	0.2–68.3	0.1–63.7	0.1–58.1	0.1–67.3
Coagulation zone volume (mL)
Mean ± SD		13.9 ± 16.4	12.0 ± 13.6	10.0 ± 9.6	3.3 ± 3.7	3.1 ± 4.7	2.9 ± 4.6	2.2 ± 3.3
Median		8.5	7.8	6.9	2.1	1.6	1.1	1.0
Range		1.6–45.1	1.4–38.3	1.4–32.1	0.1–25.5	0.1–23.4	0.1–22.8	0.1–21.2
Volume change (% vs. time 0)
Mean ± SD		+10.7 ± 18.4	+8.3 ± 23.0	−6.2 ± 27.4	−47.5 ± 21.4	−50.6 ± 24.4	−51.6 ± 27.8	−47.8 ± 33.1
Median		+7.9	+7.7	−6.9	−49.2	−53.8	−55.5	−53.2
Range		−18.3/+ 79.5	−28.0/+ 87.6	−59.5/+ 18.7	−94.7/+ 8.2	−97.7/+ 3.6	−97.7/+ 3.6	−97.2/+ 84.3
TSH (μU/mL)
Mean ± SD	1.16 ± 1.06	0.62 ± 0.81	0.96 ± 1.04	1.21 ± 1.00	1.33 ± 1.40	1.38 ± 1.57	1.17 ± 0.92	1.18 ± 0.81
Median	0.93	0.40	0.66	1.00	1.05	1.08	0.95	1.03
Range	0.41–4.2	0.00–4.35	0.00–6.46	0.00–6.76	0.00–14.23	0.00–3.67	0.43–3.98	0.38–4.00
fT3 (pg/mL)
Mean ± SD	3.32 ± 0.40	3.58 ± 1.23	3.36 ± 0.79	3.33 ± 0.62	3.28 ± 0.48	3.30 ± 0.65	3.17 ± 0.48	3.25 ± 0.48
Median	3.31	3.24	3.23	3.31	3.19	3.18	3.14	3.17
Range	2.40–4.10	1.90–8.60	1.90–8.10	2.00–8.00	1.90–5.60	2.00–3.90	2.11–4.00	2.30–4.10
fT4 (pg/mL)
Mean ± SD	11.68 ± 1.88	13.20 ± 3.32	13.63 ± 6.55	11.91 ± 8.35	10.91 ± 3.06	10.62 ± 3.23	10.25 ± 3.63	10.20 ± 3.16
Median	11.51	12.62	12.64	11.30	11.25	11.14	11.11	10.87
Range	8.30–17.40	8.40–26.51	11.05–23.64	8.05–29.66	4.84–26.50	7.94–18.56	8.32–16.04	8.12–15.94
Tg (ng/mL)
Mean ± SD	118 ± 390	5126 ± 15,635	963 ± 3376	128 ± 425	76 ± 212	77 ± 180	77 ± 101	79 ± 149
Median	41	1700	237	50	30	26	40	35
Range	0.5–530	8–210,000	0.5–47,500	0.3–4700	0.2–2750	0.2–1873	1.7–456	0.8–899

fT3, free triiodothyronine; fT4, free thyroxine; SD, standard deviation; Tg, thyroglobulin; TSH, thyroid-stimulating hormone.

Table 2.

Characteristics of 11/122 Patients Treated with Percutaneous Laser Ablation Who Had an Increase in Nodule Volume Above Initial Values During a 3-Year Follow-Up

Patient no.	Structure solid/spongiform	Time 0 volume (mL)	1 year, mL (% change)	2 years, mL (% change)	3 years, mL (% change)
1	Solid	2.8	3.0 (+7.1)	3.0 (+7.1)	3.6 (+28.6)
2	Solid	5.2	4.0 (−23.1)	3.9 (−25.0)	7.5 (+44.2)
3	Solid	7.8	3.0 (−61.5)	4.8 (−38.5)	8.3 (+6.4)
4	Solid	8.1	4.8 (−40.7)	—	8.8 (+8.6)
5	Spongiform	9.1	8.2 (−9.9)	8.0 (−12.1)	11.8 (+29.7)
6	Solid	9.9	9.1 (−8.1)	8.9 (−10.1)	12.2 (+23.2)
7	Solid	15.3	11.0 (−28.1)	15.6 (+2.0)	28.2 (+84.3)
8	Solid	21.0	19.8 (−5.7)	20.0 (−4.8)	33.2 (+58.1)
9	Solid	24.0	14.7 (−38.8)	18.2 (−24.2)	36.6 (+52.5)
10	Spongiform	27.9	26.4 (−5.4)	26.0 (−6.8)	34.6 (+24.0)
11	Spongiform	44.0	40.0 (−9.1)	39.0 (−11.4)	45.6 (+3.6)

Cytology was colloid with sheets of follicular cells without atypia (class 2, Benign) in all patients.

At day 1 and week 1, serum TSH levels significantly decreased (p ≤ 0.001) and fT4 levels significantly increased (p ≤ 0.01). After 1 month, serum TSH and fT4 levels returned to baseline and stabilized. Serum fT3 did not change after PLA. A marked Tg increase occurred at day 1 (p ≤ 0.001), and returned to baseline by 1 month. Serum Tg levels decreased 6 months after PLA procedure (p ≤ 0.01) and remained consistently below initial levels at years 1, 2, and 3 (p ≤ 0.01). Before the PLA procedure, TgAb and TPOAb were positive (>100 U/mL) in 12/122 (9.8%) and 20 of 122 patients (16.4%), respectively. Three years after PLA, the initially negative TgAb and TPOAb became positive in another 9 of 110 (8.2%) and 6 of 102 (5.9%) patients, respectively. However, there were no significant changes in mean and median TgAb and TPOAb levels (TgAb, U/mL: time 0, mean ± SD 65 ± 83, median 29; 3 years after PLA, mean ± SD 72 ± 181, median 29; TPOAb U/mL, time 0 mean ± SD 106 ± 252, median 41; 3 years after PLA mean ± SD 116 ± 272, median 37). Changes in symptom and cosmetic scores are shown in Figure 3A and B. After 3 years, symptoms improved in 89 patients (73.0%), were unchanged in 28 patients (22.9%), and worsened in 5 (4.1%). Cosmetic signs improved in 87 patients (71.3%), were unchanged in 29 patients (23.8%), and worsened in 6 (4.9%).

FIG. 3.

Symptoms (A) and cosmetic signs (B) in 122 patients treated with the PLA procedure for benign thyroid nodule at different times during the 3-year follow-up. (A) Symptom score 0 = asymptomatic; 1 = mild pressure complaint; 2 = neck constraint; 3 = neck constraint plus swallowing difficulty. (B) Cosmetic sign score 0 = nodule not visible; 1 = nodule visible with hyperextended neck; 2 = nodule visible at a distance ≤ 1 m without extending neck; 3 = nodule visible at a distance > 1 m.

Complications and side effects

The major and minor complications and side effects are summarized in Table 3. No patient required emergency basic life support, no patient required hospitalization, no patient had infection, and no antibiotic therapy was administered. During laser administration, 98 (80.3%) out of 122 patients reported no pain or significant discomfort. In the presence of intense intraoperative pain, local or radiating to the jaw, teeth, chest, or back, the laser was turned off. The fibers were re-positioned in a more central area of the nodule and the ablation procedure was completed. In patients with persisting pain, prednisone administration was prolonged for 2–4 weeks. Subsequent follow-up was uneventful. Intranodular bleeding during needle insertion was seen as a rapidly expanding hypo/anechoic signal within nodular tissue. It was blocked by swift fiber insertion and laser illumination. Intranodular bleeding did not prevent ablation procedure. Thyroid pericapsular bleeding was seen at the end of procedure as a hypoechoic layer, 5–20 mm thick, surrounding the thyroid lobe. It was asymptomatic, but extensive neck bruising occurred 5–10 days later. It disappeared in about 3 to 4 weeks. No patient needed surgical decompression. When vagal symptoms with bradycardia occurred during needle placement, the bed was tilted in Trendelenburg position and maneuvers were temporarily interrupted until spontaneous recovery, which occurred in 2–5 minutes. In one patient with no history of cardiovascular disease, a syncopal episode occurred immediately after turning on the laser. The electrocardiogram recorded 14 seconds of asystole. The anesthesiologist was alerted, but the patient had spontaneous recovery of normal heart beat. The PLA procedure was aborted and the patient had PLA in a subsequent session 3 weeks later without any incident. We interpreted the episode as being due to carotid sinus stimulation. When cough occurred (duration of cough 20′′–40′′), the fiber closest to the trachea was pulled back and the PLA procedure was completed. No patient had intraoperative dysphonia. One patient had laryngeal stridor immediately after PLA termination. US imaging showed perinodular edema. Stridor disappeared over 4 minutes. No further corticosteroids were administered after standard methyl-prednisolone bolus. Swelling with pressure symptoms lasting 4–7 days corresponded to a measurable increase in nodule volume. In the patient who had cutaneous burn, a 3 mm heath mark on the skin was visible for 1 year. In the two patients who had postoperative laryngeal dysfunction, reduction in vocal cord motility occurred 12–24 hours after PLA procedure. An additional course of corticosteroids (oral prednisone 25 mg for 2 weeks, 12.5 mg for 2 weeks, and 5 mg for 2 weeks) was administered. Indirect laryngoscopy showed vocal cord motility recovery after 6–10 weeks. Nerve compression because of perinodular edema was the most likely explanation for dysphonia. No other patient had laryngeal dysfunction either immediately after PLA procedure or at 3-year follow-up assessment. Fever occurred 2–4 days after PLA in five patients. It lasted 2–4 days and did not require any additional medication. Pseudocystic transformation occurred in six patients 2–3 weeks after the PLA procedure, manifesting as a painful sudden swelling. Drainage was associated with immediate amelioration of symptoms. Three patients had pseudocyst with fasciitis due to a leak of the fluid into the neck muscle fascia. It required further anti-inflammatory drug administration and was reabsorbed spontaneously in 3–6 months.

Table 3.

Complications and Side Effects of the Percutaneous Laser Ablation Procedure on 122 Patients with Cold, Solid Benign Thyroid Nodules

Type of reaction	No. of cases	%	SIR class ^a or equivalent ^b
Intraoperative
Pain
Mild	14	11.5	A^b
Intense	10	8.2	B^b
Bleeding
Intranodular	9	7.4	A^b
Pericapsular	3	2.5	A^b
Vasovagal reaction	4	3.3	A^b
Vasovagal reaction with 14′′ asystolia	1	0.8	A^b
Cough	6	4.9	A^b
Immediate postoperatory (within 24 hours)
Stridor	1	0.8	A^a
Swelling	11	9.0	A^a
Cutaneous burn	1	0.8	A^a
Laryngeal dysfunction	2	1.6	B^a
Periprocedural (within 30 days)
Bruise	3	2.5	A^a
Fever (37.5°C–38.5°C)	5	4.1	A^a
Persistent pain	9	7.4	B^a
Pseudocystic transformation	6	4.9	B^a
Pseudocyst with fasciitis	3	2.5	C^a

Minor complications: A = no therapy, no consequence; B = nominal therapy, no consequence; includes overnight admission for observation only.

Major complications: C = require therapy, minor hospitalization (<48 hours); D = require minor therapy, unplanned increase in level of care, hospitalization > 48 hours; E = permanent adverse sequelae; F = death.

Society of Interventional Radiology (SIR) guidelines criteria.

Not included in SIR guidelines, classified with the same criteria.

Thyroid dysfunction

One month after PLA, clinical overt hyperthyroidism developed in two patients with negative TPOAb and TgAb levels. It was associated with a transient TRAb peak (68 and 82 U/L at month 1, respectively) without any change in TPOAb and TgAb levels. The first hyperthyroid patient received methimazole (5–10 mg/day) therapy for 1 year; after methimazole withdrawal, TSH, thyroid hormone, and TRAb levels remained normal during the 3-year follow-up period. The second hyperthyroid patient received radioiodine therapy, became hypothyroid at 6 months, and was put on thyroxine replacement therapy. Two patients developed hypothyroidism 1–6 months after PLA and were put on thyroxine replacement therapy. Both hypothyroid patients had positive thyroid TPOAb and TgAb levels before PLA treatment.

Discussion

This is the largest series of patients with solid benign thyroid nodules treated with the PLA procedure. Three years is also the longest follow-up available. The limitation of this study is the retrospective, noncontrolled design. According to most authors, shrinkage of nodules is proportional to tissue ablation, which is related with laser energy administered (17,18,21,26,27). In a single study, however, low energies were reported to be effective (22). Repeat PLA sessions have little advantage (34). Our study shows that a large area of nodular thyroid tissue may be destroyed in a single session. To obtain larger ablation, Pacella et al. (35) proposed a 4 fiber square/spheric configuration technique for liver round-shaped lesions, achieving a mean coagulation volume of 15.0 ± 5.1 mL (range 18.0–25.0 mL) in a single session. Square/spheric configuration does not fit the ellipsoid anatomy of most thyroid nodules, in which length (cranio-caudal axis) is the greatest diameter, width (transverse axis) is the intermediate diameter, and thickness (antero-posterior axis) is the smallest diameter. Using the concept of multiple fiber placement, we positioned up to four needles one at the side of the other along the longitudinal, greatest diameter of thyroid nodules. A needle pull-back procedure allowed us to tailor the ablating energies to the size and shape of the nodules. The median energy delivered (7000 J) was very close to the amount of energy previously described by Pacella et al. with the 4 fiber technique used for ablating liver lesions (35). This suggests that energies delivered by the laser are reproducible for liver and thyroid tissue ablation when the same technique is used.

Reduction in nodule volume in laser studies ranged 36%–82% (17,18,20 –24,27,29,34). Our study demonstrates that PLA is effective in reducing benign thyroid nodules by 40%–60% after 3 years. Immediately after PLA procedure (days 1–7), nodules increased in size. Nodule enlargement has not formerly reported in either RF or PLA studies (9 –15,17 –19,21 –29). Thyroid tissue edema explains initial swelling. Subgroup analysis revealed a greater percent nodule decrease in small nodules. Three years after PLA procedure, however, percent volume change showed a trend to a 50% volume reduction, independently of initial size. These data show that our technique is flexible and adaptable to nodule size. As described by all authors, nodule volume shrinkage was associated with subjective and objective improvement (17 –19,21 –23,26,27,29).

RF, another technique using thermal injury to destroy tissue (36), obtains variable nodule volume reduction (9 –15). RF G14-17 electrode needles are inserted into the thyroid nodule through a transverse approach from the isthmus toward the common carotid artery (9 –15), whereas in PLA multiple optical fibers are inserted through G21 needles by a cranio-caudal approach (17 –29). Apart of the use of thinner needles, PLA would have the theoretical advantage over RF to ablate the nodule along its greatest diameter, which almost always coincides with the longitudinal axis. PLA versus RF-controlled studies would be needed to explain different results obtained with these two thermal techniques.

Complications and side effects are reported to be minimal by most authors using either RF or PLA (9 –15,17 –19,21 –24,26,27,29). In our protocol, including sedation, local anesthesia, and postoperative corticosteroid administration, side effects were limited although not negligible. Pain was the most frequent side effect. The most likely explanation for pain is parenchymal edema and thyroid capsule thermal damage. Sudden swelling and tenderness because of nodule colliquation was a side effect occurring 2–3 weeks after PLA. Liquefactive changes may also occur in liver lesions (C.M. Pacella, pers. comm.) or after thyroid high-intensity focused US ablation in thyroid ewes (8). The reason of these delayed changes may be microvessel thrombosis with subsequent progressive ischemic injury and liquefactive necrosis rather than coagulative necrosis (37). Fluid evacuation resolved swelling and tenderness in the majority of patients. In few patients fluid leaked into the neck fascia causing fasciitis, pain, and prolonged reabsorption time. Bleeding is one of major concerns in ablative procedures in the thyroid gland. All patients interrupted anticoagulant or antiplatelet treatments before PLA procedure and had normal coagulation tests. We observed intranodular bleeding, a complication that has not been described previously in ablative procedures, but that has been reported with G22-27 needles used for FNA (38). Intranodular bleeding did not prevent laser ablation. Pericapsular bleeding was asymptomatic; however, a neck bruise developed a few days later. The only report of subcapsular bleeding was in a case treated with PLA (39). RF studies with larger devices (G14-17) did not report any bleeding (9 –15).

All published studies with PLA or RF selected patients without thyroid antibodies and no effects on thyroid function and thyroid autoimmunity was reported (9 –15,17 –19,21 –24,26,27,29). Positive TgAb and TPOAb was not an exclusion criteria in our study, as autoimmune thyroiditis affects about 10% of general population and increases with age (40,41). Our study establishes that TgAb and TPOAb mean serum levels were not influenced by laser ablation. However, 3 years after PLA procedure, TgAb and TPOAb newly developed in 8.2% and 5.9% of patients, respectively. Hypothyroidism was observed in two patients with positive TgAb and TPOAb before PLA. In other two patients with negative TgAb and TPOAb, hyperthyroidism was associated with an isolated peak in TRAb levels. We do not know whether this was the natural course of disease or it was laser induced. Our study strongly suggests that thyroid function and thyroid antibodies should be monitored in all patients having PLA. Case-controlled studies are required to study thyroid autoimmunity after ablation techniques that expose thyroid antigens.

Increased serum Tg concentrations are considered a nonspecific finding, as they reflect thyroid mass, thyroid injury, and TSH receptor stimulation (42). Serum Tg concentrations were not measured in other thyroid ablation studies. In our study, Tg levels increased markedly after the PLA procedures with a parallel asymptomatic small increase in fT4 levels. It is likely that PLA-induced Tg and fT4 release from intraglandular stores. After 6 months Tg levels decreased below initial values and consistently remained low up to 3 years. The only significant change in our study population was thyroid nodule volume reduction, thus suggesting that the serum Tg reduction may represent a marker of nodule mass shrinkage. The maximum decrease in nodule volume and the maximum improvement in symptoms and clinical signs was observed after 2 years. This would be in agreement with data obtained 2 years following RF (14). Three years after ablation the mean volume of nodules showed a trend to an increase, although this was not statistically significant. A subgroup of 11 patients (9.0%) had regrowth of the nodule above the initial value. Cytologic findings in patients with nodule recurrence were colloid and sheets of follicular cells without atypia as observed in all patients treated with PLA. The most frequent characteristic of recurrent cases was the solid structure of the nodule. Extensive post-hoc analyses to observe potential factors related to success or failure of therapy are required. Patients with cold solid benign nodules undergoing PLA should be advised that PLA might not be a definitive treatment. Nodule regrowth may not prevent further PLA sessions.

In conclusion, after 3 years, PLA therapy achieved shrinkage of about 50% of the initial volume in a wide size range of benign cold thyroid nodules, with a usually consistent improvement in local symptoms and signs. Side effects and failures were few although not negligible. PLA may be a new option for the clinical management of benign thyroid nodules. Long-term controlled studies are required to establish patient eligibility criteria for routine PLA.

Footnotes

Disclosure Statement

The authors declare that they are not shareholders and do not have any financial interests in the companies mentioned in this article that would compromise the design of research, the safety, and well-being of patients, the collection and interpretation of research data, or the dissemination of research results. No funds supported this study beyond the resources of Arcispedale Santa Maria Nuova.

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