Key words
thermoablation - nodal morphology - volume reduction - therapeutic effect
Introduction
Thyroid nodules are very common in our population and are therefore of great
scientific interest. About 50% of women and 30% of men have thyroid
nodules [1]. Benign nodules
(80–95% of the thyroid nodules) are classified as cystic, complex,
and solid nodules according to their nodule morphology [2]
[3]
[4]. Most benign nodules do
not cause any symptoms, although, they are nowadays easily diagnosed by
ultrasound.
The nodules only need to be treated if they cause symptoms (feeling of pressure,
difficulty swallowing, dyspnea) or cosmetic impairments [5]
[6]. The treatments include radioiodine therapy or surgical removal;
despite their advantages, these therapy options have several side effects and are
therefore not accepted by patients. For example, bleeding, laryngeal recurrent nerve
paralysis, hypothyroidism, or infections may occur. Pregnant women or women who wish
to have children in the next few months cannot undergo radioiodine therapy [7]
[8]
[9]. Therefore, minimally
invasive thermo-ablative procedures such as HIFU, radiofrequency ablation (RFA),
microwave ablation (MWA), and laser are other alternatives and have been assessed
intensively over the past years [5]
[10]
[11]
[12]
[13]
[14]. Among the alternative thermoablative procedures, HIFU is the least
invasive and most precise [15]. In HIFU,
ultrasound rays are focused by a concave ultrasound probe to heat the tissue to 85
°C. This irreversibly causes coagulation necrosis and nodule atrophy [5]
[11]
[13]
[14]. HIFU is not skin penetrating and
therefore much more comfortable for the patient. There is no risk of infection. HIFU
is used not only for the treatment of thyroid nodules, but also for prostate cancer,
uterine myomas, and liver or bone metastases [16]
[17]
[18]. To make the structures react even
more sensitively to ultrasound, research is underway on so-called sonosentizers, for
instance, for the liver and kidney [19]
[20].
HIFU is found to be a safe and effective method to treat benign thyroid nodules [10]
[11]
[12]
[13]
[14]
[21]. It is currently
mentioned as an alternative treatment option for solid and complex nodules, but with
the caveat that further studies are needed [1]. This study investigated whether the morphology of the nodule
influences the therapeutic effect. Nodule volume is the crucial assessment parameter
of both treatment success and patient comfort, therefore, the primary criteria of
judgment was volume evaluation.
This study aimed to investigate volume reduction of solid nodules and complex nodules
in the treatment of benign thyroid nodules with HIFU and to determine the
complication rate in a long-term follow-up two-center study.
Material and methods
Study design
The study was a retrospective analysis of data in an open-label, baseline
controlled, two-center study. The study complied with the institutional review
board, ethic committees, informed consent regulation, the Declaration of
Helsinki, and local regulations.
Patients
Fifty-eight patients (50 female, 8 male) from two-centers were enrolled in the
study from 2014 to 2019. Twenty-three patients were recruited from Centrum 1
(University Hospital Frankfurt) and 35 patients were from Centrum 2
(Buergerhospital Frankfurt). The median solid nodules volume was 4.7 mL
(range 0.2–23.1 mL, n=35) and the median complex nodule
volume was 4.3 mL (range 0.13–17 mL, n=23).
Twenty-four nodules were located in the left thyroid lobe, 32 nodules in the
right thyroid lobe, and two nodules in the isthmus.
All patients were over 18 years of age. Patients were included in the study if
they had proven nonmalignant nodules, symptomatic thyroid nodules
(thyrotoxicosis, swallowing problems, pain, or hoarseness), cosmetic concerns,
and refused surgery or had proven contraindications to it. No patient was known
to have had previous therapy or thermoablative procedures. None of the patients
received RIT or surgery. The indication for HIFU was thyroid autonomy in 26
patients and pressure symptoms in 32 patients.
Treatment procedure and equipment
The HIFU therapy was performed at both centers using the EchoPulse (Teraclion,
Malakoff, France) system. The device uses a concave ultrasound head
(3 MHz) to heat a 2×9 mm focus to 80–90
°C. The therapeutic head generates 87.6–320.3 J per
sonication at the focus, in which heat is generated by absorbing the acoustic
energy and converting it to thermal energy. To heat 1 mL of the nodule,
the device needs 10 seconds.
The system automatically selects the following safety margins: 0.5 cm to
the skin, 0.3 cm to the trachea, and 0.2 cm to the carotid.
Furthermore, endangered structures are protected by a physical process –
the “heat sink”. The vessels surrounding the major nerve and
vascular tracts (from 4 mm) transpose the heat generated and thus
protect the nerves and vessels from heat-induced necrosis [11].
The exact point of the nodule treatment was defined by the doctor on the device
using a so-called voxel map. The tissue was divided into voxels by 10–20
sagittal and transverse layers.
A cooling kit was installed before any therapy. The nodule volume was measured by
the Echopulse system. This was followed by either local anesthesia with
Mecain1% or general anesthesia. Then the ultrasound probe was positioned
on the hyperextended neck, with the patient in a supine position. The sonication
was performed by the device in a screw pattern and the energy level was adjusted
after each sonication.
The device uses a laser to detect deviations between the planned focus and the
actual position of the probe. If the pattern shifted, the device automatically
stopped the current sonication and the adjustment was made. At the same time,
the doctor observed the therapy process with the diagnostic ultrasound probe.
The presence of deviations or heat bubbles indicated too high a temperature, and
the doctor had to intervene manually at any time and correct the process [5]
[10]
[11]
[12]
[13]
[14]
[22]
[23].
Baseline assessment
In all patients, a pre-ablative assessment was done. Malignancy was excluded by
cytological examination based on fine-needle aspiration biopsy (FNAB) [24]. In addition, laboratory blood
tests, 99Tc MIBI scan, and calcitonin measurement were performed. Two
pathologists were involved in the study. The 2017 Bethesda-System was used as
the pathological classification system [25]. There were no biopsies due to insufficient material.
All nodules were also examined for the position, volume, and echogenicity by
B-mode ultrasound (Sonix Touch Ultrasound System, Ultrasonix Medical
Corporation, Richmond Canada) before and at regular intervals after therapy.
Ultrasound measurements were performed by three examiners as three-dimensional
measurements [26]. Nodules with a
liquid portion>50% but≤90% of the nodule volume
were defined as a complex nodule [27]
[28].
The volume reduction is the crucial parameter for the patient's symptom
improvement and thus for the success of the therapy. Studies have shown
significant volume reduction of the nodules up to 12 months after therapy [12]. Therefore, volume reduction of
the nodules at three, six, nine, and 12 months after therapy was observed. There
were few examinations of the complex nodules at nine months follow-up.
Therefore, the nine-month follow-up was only performed for the solid nodules and
the overall study population.
Statistical analysis
The statistical analysis was done with MedCalc. Normal distribution could not be
assumed thus, statistical testing was nonparametric. Differences between the
pre-ablation volume and the time points three, six, nine, and 12 months were
compared by the Wilcoxon signed-rank test. The results were significant with
p<0.05.
Results
As shown in [Fig 1], at three
months-follow up the overall study population had an average volume reduction of
38.86% (range: 4.03%–91.16%, p<0.0001 in the
Wilcoxon test, n=25), at six months-follow-up of 42.7% (range:
7.36%–93.2%, p<0.0001, n=18), at nine
months-follow-up of 62.21% (range: 12.88%-93.2%,
p=0.0078, n=8), and at 12 months-follow-up of 61.42% (range
of 39.39%–93.2%, p>0.05, n=4) Thus,
significant differences between pre-ablative volume reduction and volume reduction
with p<0.05 in the Wilcoxon-signed-rank-test were found at the three, six,
and nine month follow-up. The percentage volume reduction of the nodules showed
large ranges.
Fig. 1 Percentage volume reduction in benign thyroid nodules after
HIFU therapy in relation to the baseline volume at the follow-up of three,
six, nine, and twelve months.
As shown in [Fig 2] and [3], at the study population with solid
nodules had an average volume reduction of 49.98% at three months (range:
4.03–91.16%, p=0.0001 in the Wilcoxon test, n=15),
46.40% at six months (range: 7.36–93.2%, p=0.001,
n=11), 65.77% at nine months (range of 39.39–93.2%,
p=0.0156, n=7) and 63.88% at 12 months (range of
39.39–93.2%, p>0.05, n=2 ) follow up. Thus,
significant differences between pre-ablative volume reduction and volume reduction
with p<0.05 in the Wilcoxon-signed-rank-test were found at three-, six-, and
nine-month follow-ups.
Fig. 2 Percentage volume reduction in solid thyroid nodules after HIFU
therapy in relation to the baseline volume at the follow-up of three, six,
nine, and twelve months.
Fig 3 The boxplots show the average percent volume reduction of benign
thyroid nodules after HIFU therapy at the time points of three, six, nine,
and twelve months follow-up divided into groups of complex and solid
nodules.
As shown in [Fig 3] and [4], the study population with complex
nodules had an average volume reduction of 35.2% at three months (range:
5.85–68.63%, p=0.002 in the Wilcoxon test, n=10),
36.89% at six months (range of 12.23–68.63%,
p=0.0156, n=7) and 63.64% at 12 months (range of
52,38–73.91%, p>0.05, n=2) of follow up. Thus,
significant differences between pre-ablative volume reduction and volume reduction
with p<0.05 in the Wilcoxon-signed-rank-test were found at the three- and
six-month follow-up.
Fig. 4 Percentage volume reduction of complex thyroid nodules after
HIFU therapy in relation to the baseline volume at the follow-up of three,
six, nine, and twelve months.
In solid nodules, the average applied energy duration was 2340 s
i. e. 39 min. In complex nodules it was 3690 s i. e.
61.5 min.
Postinterventional nodal re-growth occurred in three patients. All three patients
showed initial volume reduction in the first three months and renewed volume growth
after three months. In none of the patients did the nodules increase to the
pre-interventional size with the renewed volume increase.
The complication rate was 5.2%. No complications occurred in patients with
complex nodules. In the group of patients with solid nodules, three patients had
short-term complications. Two patients had laryngeal recurrent nerve paralysis,
which was reversible after speech therapy. One patient complained of a vocal cord
weakness three months after therapy. No long-term complications occurred.
Discussion
In our study, the overall population showed a significant volume reduction and
therefore a response to HIFU therapy. Both solid and complex nodules responded with
a significant volume reduction to the therapy. The solid nodule group had a higher
percent volume reduction in relation to baseline volume at three months and six
months. These are further important data to strengthen the evidence for HIFU therapy
of benign thyroid nodules in clinical routine.
The volume reduction of 62.21% percent achieved after nine months in the
total study population, could effectively improve the patient's symptoms
such as the feeling of pressure and problems with swallowing. It confirms the
statistically significant results of other studies on HIFU therapy of benign thyroid
nodules, which often defined a volume reduction of 50% as a therapeutic
success [15]. Since residual tissue
remains after HIFU, it was necessary to exclude malignancy in all nodules with FNAB
before treatment [24].
In solid nodules, 49.98% volume reduction was observed after three months and
a 65.77% volume reduction after nine months. Thus, solid nodules achieved a
volume reduction of 50%, which was usually defined as therapeutic success
[15]. Complex nodules in our study
achieved a volume reduction of only 35.2% after three months and
36.89% after six months. They exhibited less than 50% volume
reduction. In the present study, the therapy was overall more effective in solid
nodules. In the group comparison, no statistically significant difference could be
detected due to insufficient sample size. More studies are needed to perform a group
comparison.
Since complex nodules are more inhomogeneous and have more interfaces, they would
respond better to therapy if absorption is the decisive factor for the response to
therapy [29]
[30]
[31]. Therefore, it seems that not absorption, but possibly another
factor, such as the removal of heat is crucial for the success of therapy. The
therapeutic effect, i. e. the heating of the tissue, depends not only on the
initial process of heating but also on the removal of heat. If the heat is removed
quickly, the therapeutic effect is less. The distribution or conduction of
temperature in tissues is described by Pennes heat transfer. According to this, the
greater the temperature distribution, the less dense tissue is, the less specific
heat capacity a tissue has, the greater are thermal conductivity and the more the
blood perfusion [29]
[32]
[33]. Transferring these aspects to cystic, complex, and solid nodules, it
becomes clear that solid nodules have the least heat distribution. The heat exerted
on them has a very local effect. This means that more targeted therapy can be
performed and endangered structures can be avoided. Cystic nodules are the other
extreme. These have a very high-temperature distribution so that the energy applied
is quickly distributed or evaporates and is not so easy to control. With HIFU, only
areas the size of a grain of rice are heated. If only such a small area is heated
in
several mL of the cyst, the temperature is quickly distributed and the overall
temperature of the cyst rises only slightly. A complex nodule has cystic and solid
areas so that in some areas the effect of temperature is significant and local and
in other areas, the temperature is distributed quickly and the target area is heated
less. Therefore solid nodules should respond better to HIFU than complex ones.
A limitation of this study was that the data at the 12-months follow-up were not
significant. This was due to insufficient sample size at 12 months. Further data
would be needed to significantly assess different trends in volume reduction of
solid and complex nodules beyond six months. Another weakness of the study was the
retrospective data analysis and the small number of patients in the nine- and
twelve-month groups.
In some patients, we observed a renewed volume increase after the initial volume
reduction after therapy. What causes recurrences after therapy? It is known that
15% of benign thyroid nodules have a size progression without therapy [6]. After therapy, however, these usually
do not grow any more despite the remaining tissue. The larger the nodule is, the
more nodules a patient has; the younger a patient is and the higher the BMI of a
patient is, the higher is the probability that the nodule will grow without therapy
[6]. In the patients in our study
with the grown nodule, none of the above-listed criteria applied. It would be
necessary to clarify which factors correlate with a renewed increase in nodule
volume after therapy.
In this study, the duration of therapy of complex nodules was significantly longer,
although the patients initially had a similar median volume as the solid nodules.
Despite the longer therapy duration, they had a relatively small volume reduction.
This may be because the heat is removed too quickly in complex nodules as described
above. This could only be compensated by even higher temperatures. However, this is
not possible, because otherwise heat bubbles are created by cavitation, which would
cause complications [22]
[31]. Therefore, the same energy is used
for a longer time, but this cannot compensate for the larger heat distribution,
besides, the therapeutic effect is smaller. One solution would be to heat not only
a
small area but several areas simultaneously next to each other so that relatively
less heat is dissipated.
The fact that in our study side effects only occurred in solid nodules and none in
complex nodules underlines the hypothesis that complex nodules did not develop such
high temperatures as solid ones. Less tissue was damaged.
In other thermo-ablative procedures such as MWA and RFA, a dependence of the
therapeutic outcome on the nodule morphology has already been observed.
In MWA and RFA, cystic or complex nodules respond better to therapy than solid
nodules. In one report, MWA, volume reduction of complex nodules was 72% and
of solid nodules was 27% [34]. In
RFA, cystic nodules showed 87–93% volume reduction while that in
solid nodules was 49% [34]
[35]
[36]
[37]. Therefore, in complex
nodules, RFA or MWA should be considered more likely, since HIFU, with
36.89% volume reduction, was significantly worse than MWA and RFA.
Nonetheless, for small solid nodules, the HIFU would be preferable to MWA and RFA,
because it is more effective with a 46.40% volume reduction after six months
in solid nodules.
Conclusion
To conclude, HIFU is an effective method to treat benign solid and complex thyroid
nodules. Overall, solid nodules had more volume reduction than complex nodules
through this method. The complication rate was relatively high at 5.2% and
no long-term complications occurred. All complications occurred in patients with
solid nodules.
Based on these results, the treatment alternatives of solid and complex nodules can
be evaluated better and strategies for the optimization of HIFU therapy of complex
nodules can be discussed.
Notice
This article was changed according to the following Erratum
on February 9th 2022.
Erratum
In the above-mentioned article, the order of the authors’
names was corrected and Affiliations 2 and 3 were added.
