UNIVERSITÀ DI PISA

Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in

Medicina e Chirurgia

Scuola di Specializzazione in Radiodiagnostica

Direttore: Prof. Carlo Bartolozzi

TESI DI SPECIALIZZAZIONE

The efficacy of Radiofrequency Ablation in the treatment of benign

thyroid nodules and recurrent well-differentiated thyroid carcinomas

Relatore:

Chiar.mo Prof. Carlo Bartolozzi

Candidata:

Dr.ssa Benedetta Pontillo Contillo

ANNO ACCADEMICO 2012/2013

1

INDEX

ABSTRACT 2

INTRODUCTION 5

MATERIALS AND METHODS 8

• Patients 8

• Pre-ablation assessment 8

• Procedure 9

• Follow-up 10

• Statistical analysis 11

RESULTS 12

DISCUSSION 18

CONCLUSION 25

REFERENCES 26

2

ABSTRACT

Purpose: The aim of our study was to evaluate in our experience the effectiveness of

the Radiofrequency Ablation (RFA) in the treatment of benign thyroid nodules and

locally recurrent thyroid malignancies.

Materials and methods: The study includes 23 patients, 15 with nodular goiter (NG)

with contraindication or refusing surgery and 8 with inoperable recurrent well-

differentiated thyroid cancer (RTC). RFA was performed in a single session under

ultrasound guidance, under local anesthesia and mild sedation using 18- or 19-gauge

internally cooled, single tipped electrode with 7- and 10-mm active tips. The pre- and

post-treatment evaluations included: contrast-enhanced ultrasound (CEUS) and

unenhanced Computed Tomography (CT) study for the GNs, completed with contrast

media in patients with RTCs. Of each lesion the initial volume (V), the vascularity

and the proportion of the solid component were assessed; for NGs we also evaluated

thyroid function, local symptoms (according to a score of 0-10 severity) and a

cosmetic score defined by the radiologist according to a 1-4 scale (not palpable,

palpable but not visible, visible only during swallowing and visible in any position).

The follow-up in 21/23 patients ranged between 6 and 18 months; 2/8 patients with

RTCs did not undergo 6-months follow-up, respectively for systemic progression of

disease and onset of severe comorbidity. Volume Reduction Rate was assessed

during the follow-up and therapeutic success was defined as a> 50% VRR. Residual

vital tissue was also assessed by using CEUS or post-contrastographic CT

examinations. Complications were also evaluated.

3

For NGs we also tried whether there was a correlation between VRR at 6 months

follow-up and some parameters such as age, gender, mean energy per millilitre of

pre-treatment nodule volume, nodule initial volume, initial nodule solidity and initial

nodule vascularity.

Results: Mean V of lesions before treatment was 29.5 ± 24.7 mL for NGs (range:

5.5-90ml), and 4.7 ± 3.5 ml (range: 0.8 to 8.8 ml) for RTCs.

The mean VRR at 6, 12 and 18 months were respectively 74.3%, 79.8% and 82.3%

for NGs. At last follow-up, the therapeutic success rate of NGs was 100% (15/15).

The overall recurrence rate was 0% (0/15).

We found that volume, residual vital tissue, cosmetic score and symptom score of

NGs were significantly lower at last follow-up than before treatment (P <0.0005 for

all comparison). Initial nodule volume, vascularity and energy delivered per millilitre

of pre-treatment nodule volume demonstrated to be were significantly related to 6-

months VRR (P < 0.0001 for all analysis).

The VRR of RTCs was 68.4%, 66.4% and 64.4% during the follow-up at 6, 12 and

18 months. At last follow-up, the therapeutic success rate for RTCs was 83% (5/6)

with overall regrowth and/or recurrence rate of 0% (0/6).

In no case of NG treated with RFA was observed dysphonia; 3/6 patients with

paratracheal RCT, closely adjacent to the danger triangle of the recurrent laryngeal

nerve, have reported dysphonia (permanent in 2 cases and transient in 1 patient).

4

Conclusions: RFA demonstrated in our experience to be an effective and safe

interventional technique and may represent a viable alternative to surgery in selected

patients.

5

INTRODUCTION

Thyroid nodules are very common in clinical practice, being their prevalence largely

dependent on screening modality. It varies from 4-7% for palpable nodules to 20-

76% for nodules detected by ultrasound (US) investigation, especially due to the wide

use in clinical practice of high-resolution US technique [1-3], according to the

prevalence reported at autopsy that ranges from 50 and 65%.

The clinical significance of thyroid nodules lies in their possible association with

thyroid disfunction and compressive symptoms, but it is primarily due to their

malignant potential [1,4].

Thyroid malignancies represent only 4-6,5% of all biopsied nodules and 1% of all

cancers [1,4]; differentiated thyroid carcinoma, including papillary and follicular

subtypes, is the most common and constitues 90% of all thyroid malignancies.

Serum thyrotropin (TSH) and thyroid US are pivotal in the evaluation of thyroid

nodules, as they provide important information regarding thyroid nodule functionality

and the presence of features suspicious for malignancy.

Although no imaging modality may accurately predict the nature of every nodule,

high-resolution US is the most sensitive, easily available and cost-effective diagnostic

tool available for risk stratification for malignancy in thyroid nodules. However, fine-

needle aspiration biopsy (FNAB) currently represents the best diagnostic test to

preoperatively assess nodules nature [1,3,5].

6

Regarding to treatment, benign asymptomatic nodules are usually managed by

observation only and follow-up while the primary thyroid cancer is always the

prerogative of surgery.

If the nodule is benign but causes cosmetic problems or symptoms such as dysphagia,

foreign body sensation and hyperthiroidism or if the lesion is a local recurrence of

thyroid carcinoma, a treatment is required and surgery is usually a better choice to

remove the nodule effectively. The problem is that whereas thyroid surgery is widely

available and safe in many centres, it still carries a 2 to 10% risk of complications, it

is costly, and it may not be appropriate for a surgical high risk individual or for

someone refusing surgery [6]. If recurrent thyroid cancer is detected several years

after primary surgical intervention, significant risks may be associated with

comorbidity and with scars from previous operations; this group of patients has

undergone total thyroidectomy, radioactive iodine ablation and many have also had

lymph node dissections, thus cervical anatomic planes are distorted. A nonsurgical

and minimally invasive treatment modality is needed as an alternative in these

patients. When it refers to benign thyroid nodule but with compressive symptoms,

surgical intervention has some disadvantages such as leaving scar tissue in the neck,

for which the patient refuses surgery; moreover, surgery is not always feasible

because the patient has important comorbidities or may not be intubated for the

presence of severe tracheal compression by the goiter. Radioiodine therapy and

suppressive therapy also presented some disadvantages.

7

Thus, a nonsurgical, minimally invasive alternative for these patients is required,

being the US-guided ablative therapy no needing for general anesthesia, no scarring,

requiring earlier recovery to normal lifestyle, and burdened with fewer complications.

Ethanol Ablation (EA) [7,8] and Laser Ablation (LA) [9] have been tried previously in

such scenarios.

Since 1998, Radiofrequency Ablation (RFA) has also been introduced to ablate

thyroid malignancies and benign thyroid nodules [10]. Since that time, several papers

have been published about RFA in thyroid glands, demonstrating the efficacy and

safety of RFA for treating benign non-functioning, autonomously functioning thyroid

nodules [11-16] and local recurrence from well differentiated malignancies [17-20].

The efficacy of RFA for reducing benign nodule volume and relieving nodule-related

clinical problems has been recently confirmed by the prospective comparison study

by Baek et al. using a control group [21] and by Lim et al. that reported a mean

volume reduction rate of 93.4% in a four-years follow-up period [22].

In patients with locally recurrent thyroid cancer RFA also demonstrated to be

effective for maintaining locoregional control of their cancer [17–20], being reported a

mean volume reduction of 56–93% [19, 20].

The aim of our study was to determine the efficacy of Ultrasound-guided

Radiofrequency Ablation in our experience in the treatment of symptomatic benign

thyroid nodules and recurrent well-differentiated thyroid cancers.

8

MATERIALS AND METHODS

Patients

Twenty-three nodules in 23 patients judged ineligible for surgery or refusing surgery

were treated with single-session US-guided RFA at our Institution. Fiftheen out of 23

lesions were benign nodules in patients (12 females, 3 males; mean ± SD age, 57,8 ±

9,9 years; range, 39-73 years) with nodular goiter (NG) reporting cosmetic and/or

symptomatic problems. Eight patients (2 females, 4 males; mean ± SD age, 68 ± 9,8

years; range, 53-83 years) presented with regional recurrence from well-differentiated

thyroid carcinoma (RTC). Citologically confirmation of benign or malignant nature,

respectively, was obtained on two separate US-guided FNAB for each patient.

Pre-ablation assessment

All patients were evaluated by baseline and contrast-enhanced ultrasound (CEUS)

examination (7,5 MHz, MyLab Twice, Esaote, Italy).

Unenhanced and post-contrastographic computed tomography (CT) examination

(Light Speed VCT, General Electric, USA) of the neck was also performed for all

RTCs; baseline CT scan was also done for large benign nodules (> 20 mL).

The volume of each nodule was calculated before RF ablation as V= πabc/6 (where V

is volume, a is the largest diameter, and b and c the two other orthogonal diameters).

Nodule vascularization was assessed before treatment by evaluating lesions contrast

enhancement using three-point scale, with grade 1, 2 and 3 defined respectively as

diffusely low, inhomogeneously moderate and diffusely high vascularity.

The proportion of solid component, defined as nodular component showing contrast

9

medium uptake, was also evaluated. Fluid component of mixed type nodules was

previously aspirated in order to obtain only predominantly solid lesions (solid

component > 85%). Furthermore, all patients with NG were asked to rate pressure

symptoms on a 10-cm visual analogue scale (0–10 cm), and the physician recorded a

cosmetic grade (1, no palpable mass; 2, invisible but palpable mass; 3, mass visible

on swallowing only; and 4, easily visible mass) [23-25]. Laboratory examinations for

patients with NG included measurements of serum thyrotropin, total triiodothyronine

and free thyroxine concentrations.

Procedure

A written informed consent document, explaining possible complications, was

obtained from all patients before the procedure.

RF ablation was performed on inpatients who had been hospitalized during the

previous afternoon and discharged the morning after treatment.

Platelet count and blood coagulation tests, including prothrombin time and activated

partial thromboplastin time were required to be normal.

Before ablation, an intravenous route was made via the antecubital vein of the arm for

the intravenous administration of sedative drugs, being the procedure performed

under mild sedation. The patients were treated with 2% lidocaine for local anesthesia

at the puncture site. To prevent unnecessary scar formation, the skin was not incised.

All RF ablations were performed by using a RF generator (VIVA RF generator,

STARmed, Korea) and 18- or 19-gauge internally cooled, single tipped electrode

10

with 7- or 10-mm active tip. In this study we treated only one nodule per patient; if

the patient had a multinodular goiter, we treated the nodule of most cosmetic or

symptomatic concern. Under US guidance, we performed RF ablation of benign

nodules using transisthmic approach and moving shot technique, as previously

described [11,12,21,23]. Small regional recurrences of thyroid cancer were treated by

mostly using a vertical approach being the electrode fixed during ablation. One

puncture of the skin and thyroid capsule was made in all patients.

During the procedure, we payed special attention to the preservation of surrounding

important organs to prevent significant complication such as nerve injury.

Ablation was begun with 30–35 Watt of RF power. If a transient hyperechoic zone

did not form at the electrode tip within 5–10 s, RF power was increased in 5 W

increments to a maximum of 45 W, depending on the size of the active tip and the

internal characteristics of each nodule.

CEUS examinations were performed during procedure to better assess residual

vascularized tissue. The ablation procedure was terminated when all conceptual units

had become unenhancing zones. Immediate complications were evaluated

periprocedurally.

Follow-up

Patients were followed-up by US and CT examinations as in the pre-ablation

assessment. Mean follow-up period was 10,4 months for NGs and 13 months for

RTCs (range between 6 and 18 months).

Thyroid nodule volume and Volume Reduction Rate (VRR), calculated as [(Initial

11

Volume - Final Volume/Initial Volume) x100] were assessed. Therapeutic success

was defined as a >50 % VRR.

Residual vital tissue was also assessed by using CEUS or post-contrastografic CT

examinations.

Cosmetic and symptom scores and thyroid function tests were evaluated during the

follow-up period in the same manner as before ablation.

For NGs we also tried whether there was a correlation between VRR at 6 months

follow-up and some parameters such as age, gender, mean energy per millilitre of

pre- treatment nodule volume, initial nodule volume, initial nodule solidity and initial

nodule vascularity.

Regrowth and/or recurrence were defined as increases in nodule volume >50%

compared with previous US examination [26,27]. Complications were assessed

according to clinical signs and symptoms.

Statistical analysis

All data were analysed using the statistical software package JMP for Windows

(http://www.jmp.com). Continuous data are reported as mean ± SD (range).

Wilcoxon signed rank tests were used to compare changes in nodule volume and in

residual vital tissue before RF ablation and at each follow-up. Changes in cosmetic

and symptom scores of NGs before treatment and at last follow-up were also

evaluated by using Wilcoxon signed rank tests.

Multiple linear regression analysis were utilized for NGs to determine a correlation

between VRR at 6-months follow-up and some parameters such as age, gender, mean

12

energy per millilitre of pre- treatment nodule volume, initial nodule volume, initial

nodule solidity and initial nodule vascularity. We did not perform statystical analysis

for RTCs because of the limited population.

Differences were considered statistically significant when the P value was less than

0.05.

RESULTS

The baseline characteristics of the NGS and RTCs, and the initial cosmetic and

symptom scores of the patients are summarised in Table 1 and Table 2, respectively.

Tab.1 Baseline characteristics of benign thyroid nodules and patients’ cosmetic and symptom scores

Tab.2 Baseline characteristics of local recurrences of well-differentiated thyroid carcinomas

Follow-up period ranged between 6 and 18 months, with the mean ± SD follow-up

duration after RF ablation being 10,4± 4,6 months (range, 6– 18 months) for NGs and

13

13 ± 5,4 months (range, 6– 18 months) for RTCs.

Changes in thyroid nodule volume and residual vital tissue of NGs at each follow-up

are shown in Fig. 1. Cosmetic and symptom scores improvement at last follow-up is

illustrated in Fig. 2. The mean ± SD nodule volumes in NGs at 6, 12 and 18 months

follow-up were 7,4±8,6 ml, 4,1±2,8 ml and 4,6±2,7 ml, respectively. We found that

volume (7,2± 8,7 ml; range 0,6-37,4 ml), residual vital tissue (2,4±4,8 ml; range 0-

19,3 ml), cosmetic score (1,8±0,5) and symptom score (0,5±1,2) of NGs were

significantly lower at last follow-up than before treatment (P<0,0001 for volume and

residual vital tissue comparison; P=0,0001 and P=0,0002 for symptom and cosmetic

scores comparison, respectively).

Fig. 1 Changes of thyroid

nodule volume and

residual vital tissue before

RF ablation and at each

follow-up

The mean ± SD VRRs of NGs at 6 months, 12 months and 18 months follow-up were

74,3±9,7 % (range, 56,5–90%), 79,8± 8 % (range, 62,6–89%) and 83,0± 5,3 %

(range, 77,1–90 %), respectively (Fig.3).

14

Fig. 2 Changes of

symptom and cosmetic

scores before RF ablation

and at last follow-up.

At last follow-up, the therapeutic success rate for NGs was 100% (15/15) and the

complete necrosis (considered as the absence of residual vital tissue) was obtained in

5/15 patients (33.3 %). The overall recurrence rate was 0% (0/15).

Fig. 3 Changes of Volume

Reduction Rate (VRR)

before RF ablation and at

each follow-up

Mean total energy delivered per nodule in NGs was 36173,7±18087,3 J (range, 2303–

74818 J), and mean energy delivered per millilitre of pre-treatment nodule volume

15

(E/ml) was 1615,4±725,6 J (range, 132,4–2572,9 J).

Multiple linear regression analysis showed that initial nodule volume, vascularity and

energy delivered per millilitre of pre-treatment nodule volume were significantly

related to 6-months VRR (P<0,0001 for all analysis). Statistically significant

relationship between VRR and above-mentioned factors are shown in Fig. 4-6.

No patients experienced hypothyroidism nor hyperthyroidism after procedure. A

patient suffering from hyperthyroidism because of a Plummer nodule returned to be

euthyroid after one week to treatment and after the immediate withdrawal of therapy

with methimazole. The overall complication rate in NGs was 0% (0/15).

Fig. 4,5,6 Multiple linear regression analysis showed

a statistically significant correlation between the 6-

months VRR and some parameters such as the initial

nodule volume, the initial nodule vascularity and the

energy delivered per millilitre of pre-treatment

nodule.

16

Two out of 8 patients with RTCs did not perform 6-months follow-up because of

systemic disease progression and the occurrence of severe comorbidity, respectively.

Five out 6 patients presented with lesions in the surgical bed. Clinical findings,

changes in nodule volume and VRR for each RTC at each follow-up are reported in

Table 3 and 4. Changes in thyroid nodule volume for each RTC at 6-months, 12-

months and 18-months follow-up are shown in Fig. 7. The mean ± SD lesion volumes

in RTCs at each follow-up were 1,6±1,7 ml, 2±1,8 ml and 2,4±1,8 ml, respectively.

Fig. 7

Tab. 3

Fig. 7, Tab. 3 Characteristics and changes in nodule volume of each RTC at each follow-up

Changes of VRRs of each RTC at 6 months, 12 months and 18 months follow-up are

shown in Fig. 8. The mean ± SD VRRs were 68,4±13,4 % (range, 44,3–88,3 %),

17

66,4± 11,5 % (range, 46,6–75 %) and 64,4± 12,5 % (range, 46,6–73,3 %) at 6, 12 and

18 months follow-up, respectively.

At last follow-up, the therapeutic success rate for RTCs was 83% (5/6) and the

complete necrosis (considered as the absence of vascularized tissue) was obtained in

3/6 patients (50%). The overall regrowth and/or recurrence rate was 0% (0/6).

Fig. 8

Tab. 4

Fig. 8, Tab. 4 Characteristics and changes in VRR of each RTC at each follow-up

The overall complication rate in RTCs was 50% (3/6); major complications were

observed in 3 patients who had paratracheal lesions, closely adjacent to danger

18

triangle of recurrent laryngeal nerve (two reported permanent voice change and one

presented transient dysphonia, both due to recurrent nerve injury). No patient

experienced a life-threatening or delayed complication during follow-up.

DISCUSSION

Thyroid nodular disease is very common. The prevalence of thyroid nodules has been

reported as 20-76% at ultrasound examination, according to the prevalence reported

at autopsy that ranges from 50 and 65% [1-3,28].

If the nodule is malignant or benign but causes compressive symptoms, surgery is

usually a better choice to remove the nodule effectively. If the patient has primary

thyroid cancer, surgery is always the first choice, but if recurrent thyroid cancer is

detected several years after primary surgical intervention, significant risks may be

associated with comorbidity and with scars from previous operations; this group of

patients has undergone total thyroidectomy, radioactive iodine ablation and many

have also had lymph node dissections, thus cervical anatomic planes are distorted. A

nonsurgical and minimally invasive treatment modality is needed as an alternative in

these patients. When it refers to benign thyroid nodule but with compressive

symptoms, surgical intervention has some disadvantages such as leaving scar tissue

in the neck; moreover, in some patients with NG, surgery is not feasible because the

patient has important comorbidities or may not be intubated for the presence of

severe tracheal compression by the goiter. It calls for a nonsurgical, minimally

invasive alternative for these patients, being the US-guided ablative therapy no

19

needing for general anesthesia, no scarring, requiring earlier recovery to normal

lifestyle, and burdened with fewer complications.

Ethanol Ablation (EA) [7,8] and laser Ablation (LA) [9] have been tried previously in

such scenarios.

Radiofrequency has also been introduced to ablate thyroid malignancies and benign

thyroid nodules. In 1998, the first paper about radiofrequency ablation in thyroid

disease was published by Solbiati et al [10]. Since that time, several papers have been

published about radiofrequency ablation (RFA) in thyroid glands, demonstrating the

efficacy and safety of RFA for treating benign non-functioning, autonomously

functioning thyroid nodules [11–16] and local recurrence from well differentiated

malignancies [17-20].

In our study we treated with RFA only solid or mainly solid nodules, both benign and

malignant. The fluid component of mixed type benign nodules was previously

aspirated in order to obtain only predominantly solid or solid lesions (solid

component > 85%).

As shown by many reports RFA is more effective than EA in the treatment of solid or

mainly solid benign nodules, suggesting that solid components might be more

resistant to ethanol diffusion and that the vascularity of solid nodules favors the

drainage of ethanol; thus, the success of the procedure [29-34] results to be limited and

multiple injections of a larger amount of ethanol are required to obtain a satisfactory

degree of volume reduction. This may lead to greater patient discomfort or to adverse

effects of the procedure.

20

Some reports [12,31] demonstrated that RF ablation may be also effective and safe in

the treatment of benign predominantly cystic nodules being the volume reduction rate

quite similar (93.1% in EA and 92.2% for RF ablation) at the 6-month follow-up [35].

Nevertheless, RFA has several disadvantages compared to EA, including its high cost

and technical difficulty. Therefore, EA remains the first-line modality in the

treatment of cystic or mainly cystic thyroid nodules [36-39]; according to these

findings, we did not perform RFA for cystic or predominantly cystic benign nodules.

Previous studies also suggested the usefulness of EA in the treatment of regional

recurrent thyroid malignancies [40,41], but RF ablation demonstrated to be more

effective than EA for these lesions even when it was used to treat larger lesions [18,42].

Compared with EA, RFA has also an advantage in number of treatment sessions.

The reason for the better efficacy of RF ablation may be due to the solidity of

recurrences and to the nonuniform ethanol diffusion unable to induce necrosis to the

lesion border.

Regarding to LA, RFA results demonstrated to be superior to that of laser ablation in

a long-term follow-up, being the VRR 90–92% in RFA versus 48% in LA in a three-

years follow-up [22,23,43] and more recently, Lim et al. [22] also compared changes in

volume of benign nodules treated with RFA to those of LA; they observed a gradual

volume reduction in RFA treated nodules during follow-up, whereas nodules treated

with LA tended to increase in volume at last follow-up [21,43-45] with the latter

possibly due to the regrowth of undertreated peripheral portions of nodules [23,44,46].

RFA also seems to be safer than laser ablation [47].

21

The efficacy of RF ablation for reducing benign nodule volume and relieving nodule-

related clinical problems was recently confirmed by the prospective comparison

study by Baek et al. and using a control group [21]. In five, representative studies,

reduction of the nodule volume after RF ablation ranged from 33– 58% at one month

and from 51–85% at six months postablation [12,14,21,46]. More recently, the mean

volume reduction rate based on 111 patients with 126 benign thyroid nodules has

been reported to be 93.4% four years following RF ablation [22].

In patients with locally recurrent thyroid cancer RFA also demonstrated to be

effective for maintaining locoregional control of cancer [17-20], being reported a mean

volume reduction of 56–93% [19,20], and with 42–58% of the nodules disappearing

completely [17,18,20].

The results of our study correspond well to those study results.

The present evaluation of 23 patients demonstrated that RF ablation resulted in

significant reductions in the volumes of 15 benign thyroid nodules, as well as

improving cosmetic and/or symptomatic problems for NGs. We found that the

efficacy of RF ablation in the treatment of benign nodules was influenced by the

initial volume (being the VRR higher for smaller lesions) and vascularity of the

nodules, resulted RFA to be more effective in nodule with low grade of

vascularization. Energy delivered per millilitre of pre-treatment nodule volume also

demonstrated to be significantly related to 6-months VRR, suggesting an adequate

energy supply.

22

We suggest that the efficacy of RF ablation is explained by the moving shot

technique and straight internally cooled electrodes. For the moving shot technique,

we divided thyroid nodules into multiple small conceptual ablation units and then

performed ablation in the nodule in a unit-by-unit manner by moving the electrode

[12,23,24,46]. This technique enabled more detailed ablation of each conceptual unit and

of the periphery of the nodule showing the capacity to completely ablate the entire

nodule unlike other stationary ablation methods such as in laser ablation.

Theoretically, this technique will ablate nodules more completely because the tumor

shape is usually ellipsoid rather than round [23].

We treated all nodules in a single-session ablation, according to several previous

studies [11,13,48,49] reporting that single-session RF ablation was sufficient for

treatment of thyroid nodules, reducing nodule volume and improving cosmetic

problems and nodule-related symptoms. In our study no benign nodule presented a

regrowth during the follow-up period.

The advantage of straight internally cooled electrodes is easy movement [46], and the

advantage of an internally cooling technique is preventing carbonization [50]. This

electrode is shorter and thinner than that of a conventional electrode used in the liver,

and was designed for easy control and minimal normal tissue injury.

On the basis of previous studies [11,12,51] we proposed use of the transisthmic

approach. An electrode approach is made from the medial to the lateral aspect of a

targeted nodule, the short axis of the nodule, and RFA is performed in a transverse

ultrasound view. This method has several advantages over the long-axis approach

23

(caudocranial or craniocaudal direction) and the vertical approach [13,31,52,53], firstly

that the electrode passes through sufficient thyroid parenchyma to prevent a change

in the position of the electrode tip during swallowing or talking. Another advantage is

clear visualization of the relations of the thyroid nodule, electrode tip, and recurrent

laryngeal nerve to one another in order to minimize the risk of injury to the recurrent

laryngeal nerve.

For the 8 RTCs we treated, both transisthmic approach and vertical method were

used, by choosing as the case. We did not perform moving shot technique in the

treatment of RTCs but the electrode was held fixed during the treatment. In this way

we have exploited the heating effect due to the presence of perilesional fibrosis linked

to previous surgery and radiation therapy in the neck.

According to other investigators [17,42] we reported no recurrent disease at RF sites in

our small group of patients with RTCs with a mean follow-up of 13 months.

However, some authors [19] experienced tumoral regrowth in 2 of 15 treated cases,

including one where complete ablation was initially obtained. The factors that cause

tumor regrowth are unclear. Park at al. [19] demonstrated that there was no marked

difference in techniques such as ablation time or RF power output between the

masses that responded to therapy versus the ones that did not in their study.

They hypothesized that is likely that regrowth is related to tumour biological

behaviours. Thus, RFA is only recommended in the treatment of histologically well-

differentiated tumours, and there is no evidence of efficacy of RFA in the treatment

24

of poorly differentiated tumours or in medullary cancers. According to these findings,

we included in our study only recurrences from well-differentiated thyroid cancers.

A therapeutic success was obtained in 5 out of 6 patients (83%) because 1/6 RTC

presented a VRR <50%; this is explained by the fact that the end point of our study,

as previously suggested [17–20], was volume reduction and local control of cancer in

patients with RTCs.

One patient was lost from follow-up to the onset of severe lung infection and

respiratory failure and another patient presented disease progression in other sites

except the RF site and has been managed with systemic therapy in another Institution.

Three of our patients had dysphonia after treatment of a recurrence in the surgical

bed. Dupuy et al. [17] and Monchik et al. [18] also reported that one patient had

dysphonia after treatment of a surgical bed tumor. These findings suggest that RFA is

less safe in the surgical bed than in the lateral aspect of the neck. During RFA of the

lateral aspect of the neck, the vagus nerve can be damaged, especially when the nerve

is close to the tumor. At ultrasound examination, however, the vagus nerve is well

visualized within the carotid sheath, usually posterolateral to the common carotid

artery and posteromedial to the internal jugular vein. Careful attention to the vagus

nerve during ablation can prevent vagus nerve injury [54,55]. In contrast, in the surgical

bed, the recurrent laryngeal nerve is not visualized at ultrasound examination, and the

nerve is more vulnerable to thermal injury.

Our study had several limitations. The first limitation was a relatively short-term

follow-up period. Nodule regrowth may be possible during longterm follow-up

25

periods, thus further results should be verified. Another limitation was that our

sample size was small and might not be reflective of a larger population of

symptomatic thyroid nodules and recurrent thyroid cancers.

In addition, selection bias is inevitable. Regarding to RTCs, we treated small lesions

likely providing more favourable results. Further works are needed to fully evaluate

the RFA in inoperable RTCs because of the indolent nature of the disease and low

mortality rate.

CONCLUSION

Although surgery is the standard treatment of symptomatic benign thyroid nodules

and locally metastatic thyroid cancer, RFA is effective for symptoms relief and

locoregional control of recurrences. RFA reduced the tumor volume significantly and

demonstrated also to be a safe procedure. However, RFA is less safe for central than

for lateral neck tumors, and we recommend that caution be exercised in the treatment

of lesions that may be in close proximity to the recurrent laryngeal nerve.

26

REFERENCES 1. Papoveniuc G, Jonklaas J. Thyroid nodules. Med Clin North Am.2012; 96(2):

329-349.

2. Bomeli SR, LeBeau SO, Ferris, RL. Evaluation of a thyroid nodule. Otolaryngol

Clin North Am. 2010; 43(2): 229-238.

3. Gharib H, Papini E, Paschke R, et al. American Association of Clinical

Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid

Association Medical Guidelines for Clinical Practice for the Diagnosis and

Management of Thyroid Nodules. Endocr Pract 2010; 16 (Suppl 1): 934-941.

4. Anil G, Hedge A, Chong V. Thyroid nodules: risk stratification for malignancy

with ultrasound and guided biopsy. Cancer Imaging 2011; 11: 209-223.

5. Ito Y, Amino N, Miyauchi A. Thyroid ultrasonography. World J Surg 2010; 34:

1171-1180.

6. Gharib H, Hegedüs L, Pacella CM, et al. Nonsurgical, Image-guided, minimally

Invasive Therapy for thyroid nodules. J Clin Endocrinol Metab 2013; 98(10):

3949-3957.

7. Papini E, Pacella CM, Verde G. Percutaneous ethanol injection (PEI): what is its

role in the treatment of benign thyroid nodules? Thyroid 1995;5:147-150.

8. Lewis BD, Hay ID, Charboneau JW, et al. Percutaneous ethanol injection for

treatment of cervical lymph node metastases in patients with papillary thyroid

carcinoma. Am J Roentgenol 2002;178:699-704.

27

9. Døssing H, Bennedbaek FN, Karstrup S, et al. Benign solitary solid cold thyroid

nodules: US-guided interstitial laser photocoagulation-initial experience.

Radiology 2002; 225:53-57.

10. Solbiati L, Ierace T, Dellanoce M, et al. Percutaneous US-guided radiofrequency

ablation of metastatic lymph nodes from papillary cancer of the thyroid gland:

initial experience in two cases. Radiology 1998; 209:385.

11. Kim YS, Rhim H, Tae K, et al. Radiofrequency ablation of benign cold thyroid

nodules: initial clinical experience. Thyroid 2006;16:361-367.

12. Jeong WK, Baek JH, Rhim H et. Radiofrequency ablation of benign thyroid

nodules: safety and imaging follow-up in 236 patients. Eur Radiol 2008; 18:1244–

1250.

13. Deandrea M, Limone P, Basso E et al. US-guided percutaneous radiofrequency

thermal ablation for the treatment of solid benign hyperfunctioning or

compressive thyroid nodules. Ultrasound Med Biol 2008; 34:784–791.

14. Spiezia S, Garberoglio R, Milone F, et al. Thyroid nodules and related symptoms

are stably controlled two years after radiofrequency thermal ablation. Thyroid

2009; 19:219-225.

15. Owen RP, Silver CE, Ravikumar TS et al. Techniques for radiofrequency ablation

of head and neck tumors. Arch Otolaryngol Head Neck Surg 2004; 130:52–56.

16. Baek JH, Jeong HJ, Kim YS et al. Radiofrequency ablation for an autonomously

functioning thyroid nodule. Thyroid 2008; 18:675–676.

28

17. Dupuy DE, Monchik JM, Decrea C et al. Radiofrequency ablation of regional

recurrence from well-differentiated thyroid malignancy. Surgery 2001; 130:971–

977.

18. Monchik JM, Donatini G, Iannuccilli J et al. Radiofrequency ablation and

percutaneous ethanol injection treatment for recurrent local and distant well-

differentiated thyroid carcinoma. Ann Surg 2006; 244:296–304.

19. Park KW, Shin JH, Han BK, et al. Inoperable symptomatic recurrent thyroid

cancers: preliminary result of radiofrequency ablation. Ann Surg Oncol

2011;18:2564-2568.

20. Baek JH, Kim YS, Sung JY, et al. Locoregional control of metastatic well-

differentiated thyroid cancer by ultrasound-guided radiofrequency ablation. Am J

Roentgenol 2011;197:W331-336.

21. Baek JH, Kim YS, Lee D, et al. Benign predominantly solid thyroid nodules:

prospective study of efficacy of sonographically guided radiofrequency ablation

versus control condition. AJR Am J Roentgenol 2010;194(4)1137–1142.

22. Lim HK, Lee JH, Ha EJ, et al. Radiofrequency ablation of benign nonfunctioning

thyroid nodules: 4-year follow-up results in 111 patients. Eur Radiol 2013;

23:1044–1049.

23. Baek JH, Lee JH, Valcavi R, et al. Thermal ablation for benign thyroid nodules:

radiofrequency and laser. Korean J Radiol 2011; 12:525–540.

29

24. Ha EJ, Baek JH, Lee JH. The efficacy and complications of radiofrequency

ablation of thyroid nodules. Curr Opin Endocrinol Diabetes Obes 2011; 18:310–

314.

25. Na DG, Lee JH, Jung SL, et al. Radiofrequency ablation of benign thyroid

nodules and recurrent thyroid cancers: consensus statement and

recommendations. Korean J Radiol 2012; 13:1–9.

26. Moon WJ, Baek JH, Jung SL et al. Ultrasonography and the ultrasound-based

management of thyroid nodules: consensus statement and recommendations.

Korean J Radiol 2011; 12:1–14.

27. Cooper DS, Doherty GM, Haugen BR et al. Revised American Thyroid

Association management guidelines for patients with thyroid nodules and

differentiated thyroid cancer. Thyroid 2009;19:1167–1214.

28. Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med

1993;328:553-559.

29. Cho YS, Lee HK, Ahn IM et al. Sonographically guided ethanol sclerotherapy for

benign thyroid cysts: results in 22 patients. AJR Am J Roentgenol 2000;

174:213–216.

30. Del Prete S, Caraglia M, Russo D et al. Percutaneous ethanol injection efficacy in

the treatment of large symptomatic thyroid cystic nodules: ten-year follow-up of a

large series. Thyroid 2002; 12:815–821.

30

31. Kim JH, Lee HK, Lee JH et al. Efficacy of sonographically guided percutaneous

ethanol injection for treatment of thyroid cysts versus solid thyroid nodules. AJR

Am J Roentgenol 2003;180(6): 1723–1726.

32. Yasuda K, Ozaki O, Sugino K et al. Treatment of cystic lesions of the thyroid by

ethanol instillation. World J Surg 1992;16:958–961.

33. Jang SW, Baek JH, Kim JK, et al. How to manage the patients with unsatisfactory

results after ethanol ablation for thyroid nodules: Role of radiofrequency ablation.

Eur J Radiol 2012;81;905– 910.

34. Kim DW, Rho MH, Kim HJ, et al. Percutaneous ethanol injection for benign

cystic thyroid nodules: is aspiration of ethanol-mixed fluid advantageous? Am J

Neuroradiol 2005; 26:2122–2127.

35. Sung JY, Kim YS, Choi H, et al. Optimum first-line treatment technique for

benign cystic thyroid nodules: ethanol ablation or radiofrequency ablation? AJR

Am J Roentgenol 2011;196(2):W210–W214.

36. Lee SJ, Ahn IM. Effectiveness of percutaneous ethanol injection therapy in

benign nodular and cystic thyroid diseases: long-term follow-up experience.

Endocr J 2005; 52:455–462.

37. Sung JY, Baek JH, Kim YS, et al. One-step ethanol ablation of viscous cystic

thyroid nodules. AJR 2008; 191:1730–1733.

38. Lee JH, Kim YS, Lee D, et al. Radiofrequency Ablation (RFA) of Benign

Thyroid Nodules in Patients with Incompletely Resolved Clinical Problems after

Ethanol Ablation (EA). World J Surg 2010; 34:1488–1493.

31

39. Sung JY, Baek JH, Kim KS,, et al. Single-session treatment of benign

cystic thyroid nodules with ethanol versus radiofrequency ablation: a prospective

randomized study. Radiology 2013;269(1):293-300.

40. Lewis BD, Hay ID, Charboneau JW, et al. Percutaneous ethanol injection for

treatment of cervical lymph node metastases in patients with papillary thyroid

carcinoma. AJR Am J Roentgenol 2002; 178:699–704.

41. Heilo A, Sigstad E, Fagerlid KH, et al. Efficacy of ultrasound-guided

percutaneous ethanol injection treatment in patients with a limited number of

metastatic cervical lymph nodes from papillary thyroid carcinoma. J Clin

Endocrinol Metab 2011; 96:2750–2755.

42. Guenette JP, Monchik JM, Dupuy DE. Image-guided ablation of postsurgical

locoregional recurrence of biopsy-proven well-differentiated thyroid carcinoma.

J Vasc Interv Radiol. 2013 May;24(5):672-679.

43. Valcavi R, Riganti F, Bertani A, et al. Percutaneous laser ablation of cold benign

thyroid nodules: a 3-year follow-up study in 122 patients. Thyroid 2010;

20(11);1253–1261.

44. Døssing H, Bennedbæk FN, Hegedus L. Long-term outcome following interstitial

laser photocoagulation of benign cold thyroid nodules. Eur J Endocrinol 2011;

165:123–128.

45. Døssing H, Bennedbaek 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(3):341–345.

32

46. Baek JH, Moon WJ, Kim YS, et al. Radiofrequency ablation for the treatment of

autonomously functioning thyroid nodules. World J Surg 2009; 33:1971–1977.

47. Hegedüs L. Therapy: a new nonsurgical therapy option for benign thyroid

nodules? Nature Reviews Endocrinology 2009; 5(9); 476–478.

48. Spiezia S, Vitale G, Di Somma C, et al. Ultrasound-guided laser thermal ablation

in the treatment of autonomous hyperfunctioning thyroid nodules and

compressive nontoxic nodular goiter. Thyroid 2003; 13:941–947.

49. Huh JY, Baek JH, Choi H, et al. Symptomatic Benign Thyroid Nodules: Efficacy

of Additional Radiofrequency Ablation Treatment Session—Prospective

Randomized Study. Radiology 2012; 263(3):909-916.

50. Rhim H, Goldberg SN, Dodd GD 3rd, et al. Essential techniques for successful

radiofrequency thermal ablation of malignant hepatic tumors. RadioGraphics

2001;21(Spec Issue):S17–S35; discussion S36–S39.

51. Sung JY, Baek JH, Kim YS, et al. One-step ethanol ablation of viscous cystic

thyroid nodules. AJR 2008; 191:1730–1733.

52. Døssing H, Bennedbaek FN, Hegedus L. Ultrasound-guided interstitial laser

photocoagulation of an autonomous thyroid nodule: the introduction of a novel

alternative. Thyroid 2003; 13:885–888.

53. Bennedbaek FN, Hegedus L. Treatment of recurrent thyroid cysts with ethanol: a

randomized double-blind controlled trial. J Clin Endocrinol Metab 2003;

88:5773–5777.

33

54. Giovagnorio F, Martinoli C. Sonography of the cervical vagus nerve: normal

appearance and abnormal findings. AJR 2001; 176:745–749.

55. Tubbs RS, Loukas M, Shoja MM, et al. An unreported variation of the cervical

vagus nerve: anatomical and histological observations. Folia Morphol (Warsz)

2007; 66:155–157.