Key words high intensity focused ultrasound - thyroid nodule - thermal ablation - thyroid hormones
- thyroid function - thyroglobulin
Introduction
Thyroid nodules are relatively common in industrial nations [1 ]
[2 ]
[3 ]
[4 ]
[5 ]
[6 ] with most being benign and requiring treatment for associated symptoms such as compression,
discomfort and cosmetic concerns [7 ]
[8 ]
[9 ]. The relatively mild clinical consequences of most benign nodules suggest that standard
therapies, like surgery and radioiodine therapy (RIT), may be associated with more
harm than benefit [10 ]
[11 ]. As a result, there has been a search for alternatives to these standard treatments.
This has yielded a variety of new techniques including radiofrequency ablation [8 ], ethanol sclerotherapy [12 ], microwave ablation [7 ]
[9 ]
[13 ] and high intensity focused ultrasound (HIFU) ablation. While some of these alternative
techniques have already been established in clinical practice [14 ], a majority have drawbacks that include induction of serious immune reactions such
as Graves’ disease, scar formation, hypothyroidism and hyperthyroidism, thyrotoxicosis
and inflammation [10 ]
[11 ]
[12 ]
[13 ]
[14 ]
[15 ]
[16 ]
[17 ]
[18 ].
Of existing alternatives to standard therapies, HIFU appears to be one of the most
promising in that its advantages include: (a) non-invasiveness, (b) patient wellbeing
due to avoidance of scar formation (c) low risk of immune responses as will be discussed
below, (d) accuracy and (e) ease of use, the latter two based on our own clinical
experience. HIFU is already widely applied in clinical practice and is used to treat,
among other diseases, breast lesions [19 ], uterine fibroids [20 ] and prostate cancer [21 ]. It is also further being developed to treat kidney and liver tumors [22 ]. However, to our knowledge there have been only few published studies except our
own recent publications [23 ]
[24 ]
[25 ] investigating the ablation of human thyroid tissue with HIFU [26 ]
[27 ]
[28 ] and few other publications describing preclinical work in the area [28 ]
[29 ]
[30 ].
The objective of the current study was to assess HIFU’s effectiveness in reducing
nodule volume while preserving thyroid function, as measured by thyroid hormone and
relevant antibodies, and so to provide much needed additional data on procedure outcome
in the indication. A successful treatment in this study was achieved if the following
criteria were achieved: (a) volume reduction > 30 %, (b) symptom score improvement,
(c) euthyroid hormone status.
Materials and Methods
Patients
Patients were enrolled at the nuclear medicine department of the University Hospital
Frankfurt. Eligible patients had a symptomatic thyroid nodule and cosmetic concerns
and had either refused surgery or were contraindicated for it. Patients were excluded
for having asymptomatic nodules, nodule volume exceeding 10 ml, histological evidence
for malignancy or positive Tc-99 m MIBI uptake in cold nodules or conspicuous calcitonin
measurement.
12 patients (9 females) whose average age was 56.9 years (37 – 81) were treated with
HIFU in an ambulatory setting. All patients had a single benign thyroid nodule treated
in one HIFU session. The median nodular outline volume (NOV) was 3.4 ml (range 0.6 – 5.0 ml).
Study Design
This was a single-arm, open-label, baseline control study. The study complied with
institutional review board ethics committees, informed consent regulations, International
Committee on Harmonization Good Clinical Practice Guidelines, the Declaration of Helsinki,
and local regulations.
Treatment Procedure and Equipment
The system used in this study (Echopulse® THC900 888-H, THERACLION SA, Malakoff – France) has two separate ultrasound systems.
The imaging system works between frequencies of 7.5 and 12 MHz and the therapeutic
system with frequencies of 3 MHz, reaching temperatures approximately 80 – 90 °C.
Heat is produced by absorption of acoustic energy and its conversion into thermal
energy.
A probe with a maximal penetration depth of 1.5 cm and an exchangeable cooling kit
was used. The system automatically selected the following safety margins: (a) 0.5 cm
from the skin, (b) at least 0.3 cm from the trachea and (c) 0.2 cm from the carotid.
The mean output per treated voxel varied between 87.6 and 192.8 W.
Before each treatment, a cooling kit was installed and the system underwent a general
test of function. The nodular volume was measured using US ([Fig. 1 ]). Local anesthesia (Mecain 1 %) was given, followed by positioning of the ultrasound
probe on the hyperextended neck and primary marking of relevant structures. The system
automatically generated a voxel map of the intended nodule and the marked structures
around it. Following the computed voxel map in a screw pattern while adjusting the
energy level, the system executed ablation by automatically alternating a four-second
treatment beam with a cooling pause and positioning. Throughout the procedure the
voxel map and sonographic images, showing the actual and planned images of the current
voxel, were visible to enable control of the ultrasound probe location.
Fig. 1 Example of ultrasound imaging of a thyroid nodule. Part A shows the nodule pre-ablation and part B three months post-ablation. Light blue crosses mark the nodules. White arrows mark
the carotid artery. In this example a successful volume reduction of 2.8 ml was achieved.Abb. 1 Ein Beispielbild für die Ultraschallkontrolle eines Schilddrüsenknotens. Die linke
Bildhälfte (mit A markiert) stellt den Knoten vor der Behandlung durch HIFU dar, die rechte Bildhälfte
(mit B markiert) zeigt die Ultraschallkontrolle 3 Monate nach der Ablation. Die hellblauen
Kreuze markieren den Knoten. Die weißen Pfeile zeigen auf die Arteria Carotis. In
diesem Beispiel konnte eine Volumenreduktion von 2,8 ml erreicht werden.
Throughout the treatment it was possible to manually pause, reposition, select or
remove particular voxels and terminate the treatment. If patient movement occurred
during a beam, a laser-controlled movement detector directed at the laryngeal prominence
automatically stopped the treatment and lead to manual repositioning or recalibration
of the measured laser distance.
Baseline Assessment and Endpoints
All patients underwent a pre-ablation assessment, including laboratory blood tests,
ultrasound imaging and fine-needle aspiration biopsy of the targeted nodule.
B-mode ultrasound (Sonix Touch Ultrasound system, Ultrasonix Medical Corporation,
Richmond, Canada) was used to evaluate the volume, size, number and composition of
the nodules.
Serum levels were determined with commercially available immunoradiometric assay and
radioimmunoassay kits. Laboratory blood tests included a complete thyroid hormone
status with triiodothyronine (T3, normal range: 1.0 – 3.3 nmol/L) determined by RIA
(T3[125 I] RIA Kit, Izotop, Budapest, Hungary), thyroxine (T4, normal range: 55 – 170 nmol/L)
determined by RIA (T4[125 I] RIA Kit, Izotop, Budapest, Hungary), thyrotropin (TSH, normal range: 0.3 – 4.0
mE/L) determined by IRMA (SELco® TSH rapid, Medipan GmbH, Dahlewitz, Germany) and thyroglobulin (Tg, normal range:
2 – 70 ng/mL) determined by IRMA (Riason® Tg c. t., Iason GmbH, Graz-Seiersberg, Austria).
Calcitonin level, blood count and coagulation diagnostic were measured.
The presence of antibodies was also examined, specifically those against thyroid peroxidase
(TPOAbs, positive: > 50 U/mL) determined by RIA (anti-TPO magnum, Medipan GmbH, Dahlewitz,
Germany), thyreoglobulin (TAbs, positive: > 50 U/mL) determined by RIA (anti-Tg magnum,
Medipan GmbH, Dahlewitz, Germany) and thyrotropin receptor (TRAbs, positive: > 1.5 IU/L)
determined by RIA (TRAK Human RIA, Brahms GmbH, Henningsdorf, Germany).
Patients with “cold” nodules were evaluated with a Tc-99 m methoxy-isobutyl-isonitrile
(MIBI) scan to exclude malignancy. Images were taken 10 and 60 minutes after injection
of 500 MBq (13.5 mCi) Tc-99 m MIBI. Further a fine-needle aspiration biopsy was performed.
No evidence of malignant transformation was found in any of the subjects.
The patients had follow-up laboratory blood tests at 24 hours and 3 months after ablation
treatment.
Statistical Analysis
Statistical analyses were done with the R statistical software [29 ]. Because of the small sample size and the fact that normality could not be assumed,
all statistical testing was non-parametric. Differences between time points were compared
by the Wilcoxon sign-rank test and correlation using Kendall’s tau.
Results
Safety and Tolerability
HIFU treatment sessions were completed successfully for all twelve patients. All patients
tolerated the treatment and interruption was not necessary.
Laboratory Tests
With the exception of thyroglobulin (hTg), no laboratory parameter, antibody measurement
or blood count changed significantly at all follow-ups.
Thyroglobulin levels increased significantly (p < 0.05) 24 hours after ablation and
decreased significantly at the 3-month follow-up relative to the 24-hour time point
(p < 0.05). Comparison of 3-month hTg values to the baseline was not significant ([Fig. 2 ]). Descriptive statistics for serum levels are provided in [Table 1 ].
Fig. 2 Boxplots of hTg serum levels. The increase of hTg levels 24 hours after ablation
and the following decrease three months after ablation are significant (p < 0.05).Abb. 2 Diese Grafik zeigt einen Boxplot der hTg- Blutserum-Werte. Sowohl der Anstieg der
Werte 24 Stunden nach der Ablation, als auch der darauf folgende Rückgang drei Monate
nach der Ablation sind signifikant (p < 0,05).
Table 1
Thyroid function parameter medians at baseline and follow-ups.
parameter
baseline
24 hours after HIFU
3 months after HIFU
T3 [nmol/L]
1.7 (1.4 – 2.3)
1.7 (0.9 – 2.7)
1.5 (1 – 2.2)
T4 [nmol/L]
84 (69 – 144)
92 (74 – 146)
87 (60 – 164)
TSH [mE/L]
0.9 (0.5 – 5.6)
0.7 (0.1 – 3.0)
1.2 (0.1 – 1.8)
hTg [ng/mL]
29.6 (0.1 – 459)
702.0[1 ] (28.9 – 3431.0)
15.31 (0.09 – 155)
TPOAbs [U/mL]
10 (6 – 1119)
12 (6 – 986)
7 (3 – 791)
TAbs [U/mL]
9 (5 – 110)
7 (5 – 63)
9 (3 – 108)
TRAbs [IU/L]
0.02 (0 – 0.92)
0.30 (0 – 0.74)
0.3 (0 – 0.74)
Median laboratory parameters at baseline and follow-ups. Normal ranges of hormones
and antibodies are: T3: 1.0 – 3.3 nmol/L, T4: 55 – 170 nmol/L, TSH: 0.3 – 4.0 mE/L,
hTg: < 1 after thyroidectomy, TRAbs: positive > 1.5 IU/L, TAbs: positive > 50 U/mL,
TPO > 50 U/mL. The increase of hTg levels 24 hours after ablation and the following
decrease 3 months after ablation are significant (p < 0.05). Data are presented as
median and range. Blood count, coagulation diagnostics and calcitonin were within
normal limits in all patients at all dates of measurement.
Die Tabelle zeigt die Mittel der Laborparameter zum Zeitpunkt vor der HIFU-Therapie
und bei den Kontrollen. Der normale Bereich der Hormone und Antikörper sind: T3: 1,0 – 3,3 nmol/L,
T4: 55 – 170 nmol/L, TSH: 0.3 – 4.0 mE/L, hTg: < 1 nach Thyreoidektomie, TRAbs: positiv
> 1,5 IU/L, TAbs: positiv > 50 U/mL, TPO > 50 U/mL. Die einzigen signifikanten Veränderungen
waren im hTg-Wert zu beobachten (p < 0,05). Die Daten sind als Median und Bereich
präsentiert. Das Blutbild, die Gerinnungsdiagnostik und die Calcitoninwerte waren
bei allen Patienten an allen Messungen im Referenzbereich.
1 p < 0.05
Efficacy
The median reduction of the NOV at the three-month follow-up was 55 % (p < 0.05).
In three patients the therapy was not successful, because a volume reduction of more
than 30 % was not achieved.
Antibody Measurement
No patient showed signs of Hashimoto’s thyroiditis or Grave’s disease. Yet one patient
had elevated levels of anti-TPO before HIFU. After HIFU the levels remained stable.
Antibody measurement is summarized in [Table 1 ].
Discussion
HIFU is currently the least invasive method for the treatment of thyroid nodules,
with the most favorable safety profile, posing low risk for infection and other side
effects [27 ]. The study presented in this article found no indication that HIFU either interferes
with thyroid gland function or induces thyrotoxicosis. Furthermore, no indications
for serious thyroid diseases like Graves’ disease or Hashimoto’s thyroiditis were
found. The hormone status of all patients remained stable and substitution was not
necessary.
HIFU ablates with temperatures of about 80 to 85 °C. Irreversible tissue damage by
heat occurs at temperatures higher than 60 °C [30 ]
[31 ] while high temperatures under 60 °C induce reversible damage, with a high risk of
leaking functional thyroid hormones inducing transient thyrotoxicosis [16 ]. Other thermal ablative treatments use rather large ablation areas and a long ablation
time and thus leak significant energy into the surrounding tissue.
In comparison to other thermal ablative treatments, HIFU works with small focal points,
great accuracy, short ablation times and a constant cooling system whereby very little
energy is spread to the surrounding not targeted tissue [26 ]
[27 ]
[28 ]. This is likely the reason that there have yet to be reports of HIFU inducing thyrotoxicosis,
which may in fact not occur at all when using this procedure. Adding to the safety
of the procedure is that structures like blood vessels or the trachea are protected
by automatic safety margins and planning accuracy.
A successful volume reduction of more than 30 % of the pre-ablative volume was achieved
in 9 of the 12 patients in this study. However, it is possible that a further volume
reduction will be observed at later follow-ups, since not all damaged tissue might
be biologically degraded 3 months after ablation.
Thyroglobulin serum levels were measured to evaluate the success of ablation. In clinical
diagnosis thyroglobulin constitutes a tumor marker, but it can also be measured to
assess thyroid mass or damage to thyroid tissue [27 ]
[32 ]. Thyroglobulin levels increased significantly from baseline to 24 hours and subsequently
stabilized at the 3-month follow-up. Since all other laboratory parameters remained
stable and no post-ablative increases in antibodies were found, it is possible that
HIFU preserves thyroid gland function and does not induce antibodies against thyroid
tissue. It should be noted that while non-significance in a small sample such as ours
does not prove a lack of change, the similarity of pre and post values on these parameters
supports this conclusion.
At the same time, as it currently stands, HIFU treatment for this indication has some
drawbacks. Most importantly, HIFU treatment is currently limited to nodules that are
smaller than 10 ml. Such was the case in this study and worse results are obtained
with bigger nodules. One possible solution for achieving sufficient volume reduction
with bigger nodules may be multiple HIFU sessions given at appropriately spaced intervals.
Unfortunately there has, to our knowledge, been no study investigating the effects
of multiple HIFU sessions. However, the automatic safety margins and anatomical proximity
to sensitive structures still represents a limiting factor to treatment success, especially
in smaller nodules close to the trachea or the carotid artery, but a possible solution
for this problem could lie in the variation of the treatment angle, or liquid infiltration,
e. g. local anesthesia in the space between the nodule and the sensitive structure.
Conclusion
HIFU treatment in benign thyroid nodules is safe, effective and easy to use. The procedure
preserves thyroid gland function and there is no indication of it causing autoimmune
diseases or thyrotoxicosis. Volume reduction is significant and in most cases sufficient.
Due to small sample size and missing long-term outcome, findings of this study need
to be verified by larger studies.
