# High-Intensity Focused Ultrasound in Small Renal Masses

Authors: Jose Rubio Briones; Argimiro Collado Serra; Alvaro Gómez-Ferrer Lozano; Juan Casanova Ramón-Borja; Inmaculada Iborra Juan; Eduardo Solsona Narbón
Journal: Advances in Urology
 (2008)

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## Abstract

High-intensity focused ultrasound (HIFU) competes with radiofrequency and cryotherapy for the treatment of small renal masses as a third option among ablative approaches. As an emerging technique, its possible percutaneous or laparoscopic application, low discomfort to the patient and the absence of complications make this technology attractive for the management of small renal masses. This manuscript will focus on the principles, basic research and clinical applications of HIFU in small renal masses, reviewing the present literature. Therapeutic results are controversial and from an clinical view, HIFU must be considered a technique under investigation at present time. Further research is needed to settle its real indications in the management of small renal masses; maybe technical improvements will certainly facilitate its use in the management of small renal masses in the near future.


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## Body

## 1. Introduction

We are
facing a rapid
increase of
incidentally  detected small renal masses
(SRMs) nowadays
[1, 2], prompting us
to face many different clinical scenarios and probably minimally invasive
ablative techniques will  find their role in those unfit patients who are not
operable and do not accept a partial nephrectomy or a watchful waiting policy [3]
in case of a possible renal cell carcinoma (RCC) diagnosed probably
incidentally [4].High-intensity focused
ultrasound (HIFU) induces thermal damage to the targeted tissue without the
need of the insertion
of a probe into the tissue, thus being the most real “minimally invasive”
proposed technique among the ablative treatments for small renal masses (SRMs).This manuscript will
focus on the principles, basic research, and clinical applications of HIFU in
small renal masses, reviewing the present literature and analyzing HIFU as a
possible treatment for SRM, recognizing no experience in its use for any renal masses
by our group.


## 2. Material and Methods

We reviewed PubMed with
no limit on time, searching for papers in English or Spanish, using HIFU and renal
or HIFU and kidney as key words. We included the literature published on HIFU
both in the experimental and clinical settings.


## 3. Principles and Technique

The principle of HIFU
resembles the one for ultrasound (US), but a higher intensity is
used. Ultrasound is progressively absorbed by the tissue and its mechanical
energy converted to heat. At a high and focused strategy, the generated heat
denatures proteins and produces coagulative necrosis, objectives obtained when
temperature reaches65°C in renal lesions [5]. The induction of thermal necrosis will depend on several
factors: the applied power, the US
frequency, transducer characteristics (shape, type, size, and number of
probes), exposure time, spatial distribution of the field, absorption
properties of the tissue, attenuation in the intervening tissue, acoustic
reflection and refraction, and  finally the perfusion rate in the targeted
tissue.  Different necrosis
rates were shown (volume of ablated tissue per 1 second isonication) for different organs, and for
example, the kidney has a lower necrosis rate than the liver [6].As a technique under development, there are no
standard recommendations for its application and this is a point under vast
research. Initially, extracorporeal HIFU generators used multiple piezoelectric
elements located in a concave disk, generating intensities of >10000 W/cm2
which were derived
in cavitation lesions, limitating its use in humans [7]. Nowadays, HIFU systems
use single transducers, focused by acoustic lenses or by being concave. As the
focal lengths are smaller, frequencies of 3-4 MHz can be
achieved, producing smaller but better defined lesions. Modern HIFU devices
obtain focal depths of 10–16 cm; the focal
zones are cigar shaped and the volume ablated depends on power intensity,
duration of application, and location of pulses. All this equipment is
accompanied by US regular probes trying to control the effectiveness of the
HIFU application; interestingly, as power intensity increases (5–20 kW/cm2),
a cavitation phenomenon appears which permits a target point to monitor HIFU
effects [8]. An excellent
summary on physical principles and devices of HIFU
[9] has recently been
published.In the extracorporeal
approach, frequencies of 1–1.8 MHz are used
in an attempt to increase penetration; in this range, renal thermal lesions
were observed in  animal models [10, 11]. In the
clinical setting, two
systems for  extracorporeal HIFU have been tested. First, from Storz
Medical (Storz; Schaffhausen, Switzerland), we use a
1 MHz piezo element focused at a depth of 100 mm with a parabolic reflector of
10 cm aperture. An integrated 3.5 MHz B-mode US
transducer
permits inline imaging of the area to treat. The US
beam is coupled into the body by
a flexible polyurethane cushion filled with degassed water at 16°C, witch permits
the variation of the
skin-focal spot distance altering its filling [12]. The second HIFU therapeutic
system was designed by Chonqing Haifu CO. Ltd (Chonqing, China);
it is composed by a patient table, an operating console, and a treatment unit,
situated under the table within a basin filled with degassed water to couple
with US delivered to the patient, who lies over the water bath. Exchangeable
ellipsoidal transducers of 12 or 15 cm diameter are installed in the water bath
around a central 3.5 MHz diagnostic transducer. This system permits frequencies
of 0.5, 1.2, and 1.5 MHz and focal lengths of 100–160 mm depending
on the transducer used. Following the treatment protocol and by exposing the
targeted areas up to six times, the authors achieve an estimated site intensity
of up to 20000 W/cm2, enough to create cavitation and even bubble formation on
real-time diagnostic imaging, which authors propose as successful tissue
ablation marker [13].Due to the problems with
extracorporeal HIFU applications that we will further comment on, the equipment
moved into the  laparoscopic field. In porcine
models, it was
modified with acceptable partial kidney
ablation  with no damage
to surrounding not targeted tissues [14].
In phase
I study, this approach was attempted in the human setting, using conventional
lap isolation of the SRM through four 12 mm access ports; authors used
intraoperative renal power Doppler US with a 10 Hz laparoscopic US probe (BK
Medical, Denmark) to  locate the SRM. They then changed one of the ports to an
18 mm port (Ethicon; San Angelo, Tx, USA) to introduce the laparoscopic HIFU system (Sonatherm, Misonix
Inc., Fiarmigdale, NY, USA), which is composed by a treatment console, an
articulated probe arm,
a pomp unit, and
the laparoscopic probe (covered with a system which permits cooling with
gas-free cold water) [15]. HIFU energy is delivered by a truncated spherical
shell 4 MHz transducer with a 30×13mm aperture and a 35 mm focal length. One of
the best improvements of this approach, compared to the percutaneous one, is
that the probe works in direct contact with the SRM and real-time imaging,
based on qualitative assess on hyperechoic changes resulting from boiling and
cavitation events, permitting
direct control of the procedure with the 12 mm transducer aligned confocally
with the HIFU transducer. The procedure was calibrated resembling the results
obtained in animal models research to ablate tissue at an average rate of 0.6 cm3/min at typical power level between 30–38 W [14, 16].


## 4. Results

We found 42 manuscripts using HIFU and
renal/kidney as key words. HIFU has been extensively used in other organs,
targeted to malignant and nonmalignant tissues: brain, breast, eye, prostate,
bladder, uterus, liver, and so forth, showing no increase in cell dissemination
[17–20]. An
attractive indication for tumour in a solitary testis has been recently
published with acceptable results [21].


### 4.1. Pathological Assessment

The thermal damage
produced by HIFU causes progressive tissue changes depending on the time when
the pathological study is done. Immediately after its application in a porcine
model, the tissue demonstrated intense congestion, hyperaemia, and alterations
of the micropapillaries, and electron microscopy showed alterations of the mitochondria,
ribosomes, and lysozymes. At day 2, necrosis starts to be seen within an
intense area of hyperaemia and congestion which results in complete necrosis at
day 7. Finally, at day 90, a complete fibrosis of the targeted area is observed
[22]. On healthy human kidney, haemorrhages were seen in 15 out of 19 cases and
microscopically, it was shown that they were caused by fibre ruptures in the
wall of small vessels [23]. In papers where
SRMs have been excised after HIFU application,
“severe thermal tissue damage” has been defined as intravascular disruption of
erythrocyte membranes, vacuolisation of tumour and arterial smooth muscle
cells, pycnosis and elongation of tumour cell nuclei, rupture of tumour cell
membranes, and cell detachment, changes which correspond to complete tissue
necrosis if the time elapsed from HIFU application and specimen removal is
longer [24]. Negative NADH staining in snap-frozen tissue obtained before
tissue fixation with formaldehyde after HIFU treatment also reaffirms
irreversible heat damage [15, 24].


### 4.2. Results in the Percutaneous Approach

Linke et al. were the first to treat a
kidney of a rabbit using extracorporeal HIFU [25]. When applied percutaneously
in a rabbit model, it was clearly showed that only 2 out of 9 tumours showed
well-demarcated effects of ablation [26]. Watkin et al. treated 18-pig kidneys with acute damage detected in 67% [11].
In a canine model, HIFU application with 400 W power and 4-second pulse
duration and a calculated site intensity of 1430 W/h obtained coagulative
necrosis of variable degree in the targeted area [12]. Recently, the use of
microbubbles injected before percutaneous HIFU isonication of goat kidneys
showed better necrosis rates than direct HIFU application [13].In humans, phase II study using the
Storz system was conducted by the University of Vienna. Sixteen renal
tumours were treated with HIFU, two with curative intent and 14 were subsequently
removed. Examination of the specimens showed poor results in terms of
therapeutic effect, as necrosis was found only in 9 out of 14 cases, all of
which had been exposed to the highest site intensities, and the histologically
damaged tissue only composed 15–35% of the
targeted tissue [27]. In another phase II study, Häcker et al. treated
19 patients with RCC before nephrectomy, focusing HIFU to
healthy renal tissue; after immediate removal of the kidney, they observed
variable but limited pathological signs of thermal damage, as for example
haemorrhages, just in 15 out of 19 specimens, but these effects could not be
correlated to the energy administered and lesion size did never reach the
targeted volume [23].When using
the Chongqing
system,
Wu et al. applied percutaneous HIFU with a palliative intent in 13 advanced
RCC, having shown clinical improvement (less pain and disappearance of
haematuria) in most of the treated patients, although treatment was considered
incomplete in 10 patients [18]. Similar disappointing results were published
from UK,
where 8 patients were treated with a similar system and only 4 out of 6 kidneys showed
radiological evidence of treatment effect on MRI 12 days after HIFU application
and just 1 out of 4 removed kidneys showed histological confirmed ablation [17].
This group is currently undergoing a prospective, nonrandomized clinical trial
of percutaneous HIFU in the treatment of SRM, looking at histological outcome
in resected tumours in one arm and following the ablated tumours with contrast
enhanced MRI in the
other arm [28].


### 4.3. Results in the Laparoscopic Approach

In a
recently published clinical phase I study, the laparoscopic HIFU approach
previously described was applied to 10 patients with solitary renal masses. Two
of them had 9 cm tumours and HIFU was applied just as marker lesion before
radical laparoscopic nephrectomy; the rest had SRM with a median size of 22 mm
and were treated with a “curative intent” applying HIFU to the entire tumour
with a margin of 2-3 mm of
surrounding parenchyma. Seven of these tumours were operated afterwards by
means of a laparoscopic partial nephrectomy and one was left in situ in a
patient with high comorbidities. In the SRM subgroup, a median HIFU exposure
time of 19 minutes (range 8–42) was used. The
first two patients showed, in the subsequent pathological examination, just a 2-3 mm of vital
tissue adjacent to where the HIFU probe was approximated with the rest of the
tumour with thermal necrosis; the authors explained this phenomenon to an
excessive cooling of the probe, and changing this parameter, they did not
observe it again in the remaining cases, although a patient showed a 20% central area with no
thermal effects, showing complete thermal necrosis in the 4 remaining removed cases
(57%). The nonexcised tumour
was successfully treated attending to real-time US
data,
examination of core biopsies showing thermal necrosis, and follow-up CT scans
up to 6 months showing no constraint
enhancement and shrinking of the lesion [15].


### 4.4. Complications

There have
been just two severe complications due to HIFU application in the abdominal
cavity in humans: a superior mesenteric artery infarction and a perforation of
the terminal ileum, but both were after treatment of recurrent or metastatic
colon carcinoma [29]. When focused to kidneys, no serious side effects have
been shown [27]; just 2 patients had grade III skin lesions [28], but the most
common type of skin toxicity is less than 1cm blister or track at the treatment
site [17]. Changes in laboratory tests are also nonsignificant
[17, 18].


## 4.1. Pathological Assessment

The thermal damage
produced by HIFU causes progressive tissue changes depending on the time when
the pathological study is done. Immediately after its application in a porcine
model, the tissue demonstrated intense congestion, hyperaemia, and alterations
of the micropapillaries, and electron microscopy showed alterations of the mitochondria,
ribosomes, and lysozymes. At day 2, necrosis starts to be seen within an
intense area of hyperaemia and congestion which results in complete necrosis at
day 7. Finally, at day 90, a complete fibrosis of the targeted area is observed
[22]. On healthy human kidney, haemorrhages were seen in 15 out of 19 cases and
microscopically, it was shown that they were caused by fibre ruptures in the
wall of small vessels [23]. In papers where
SRMs have been excised after HIFU application,
“severe thermal tissue damage” has been defined as intravascular disruption of
erythrocyte membranes, vacuolisation of tumour and arterial smooth muscle
cells, pycnosis and elongation of tumour cell nuclei, rupture of tumour cell
membranes, and cell detachment, changes which correspond to complete tissue
necrosis if the time elapsed from HIFU application and specimen removal is
longer [24]. Negative NADH staining in snap-frozen tissue obtained before
tissue fixation with formaldehyde after HIFU treatment also reaffirms
irreversible heat damage [15, 24].


## 4.2. Results in the Percutaneous Approach

Linke et al. were the first to treat a
kidney of a rabbit using extracorporeal HIFU [25]. When applied percutaneously
in a rabbit model, it was clearly showed that only 2 out of 9 tumours showed
well-demarcated effects of ablation [26]. Watkin et al. treated 18-pig kidneys with acute damage detected in 67% [11].
In a canine model, HIFU application with 400 W power and 4-second pulse
duration and a calculated site intensity of 1430 W/h obtained coagulative
necrosis of variable degree in the targeted area [12]. Recently, the use of
microbubbles injected before percutaneous HIFU isonication of goat kidneys
showed better necrosis rates than direct HIFU application [13].In humans, phase II study using the
Storz system was conducted by the University of Vienna. Sixteen renal
tumours were treated with HIFU, two with curative intent and 14 were subsequently
removed. Examination of the specimens showed poor results in terms of
therapeutic effect, as necrosis was found only in 9 out of 14 cases, all of
which had been exposed to the highest site intensities, and the histologically
damaged tissue only composed 15–35% of the
targeted tissue [27]. In another phase II study, Häcker et al. treated
19 patients with RCC before nephrectomy, focusing HIFU to
healthy renal tissue; after immediate removal of the kidney, they observed
variable but limited pathological signs of thermal damage, as for example
haemorrhages, just in 15 out of 19 specimens, but these effects could not be
correlated to the energy administered and lesion size did never reach the
targeted volume [23].When using
the Chongqing
system,
Wu et al. applied percutaneous HIFU with a palliative intent in 13 advanced
RCC, having shown clinical improvement (less pain and disappearance of
haematuria) in most of the treated patients, although treatment was considered
incomplete in 10 patients [18]. Similar disappointing results were published
from UK,
where 8 patients were treated with a similar system and only 4 out of 6 kidneys showed
radiological evidence of treatment effect on MRI 12 days after HIFU application
and just 1 out of 4 removed kidneys showed histological confirmed ablation [17].
This group is currently undergoing a prospective, nonrandomized clinical trial
of percutaneous HIFU in the treatment of SRM, looking at histological outcome
in resected tumours in one arm and following the ablated tumours with contrast
enhanced MRI in the
other arm [28].


## 4.3. Results in the Laparoscopic Approach

In a
recently published clinical phase I study, the laparoscopic HIFU approach
previously described was applied to 10 patients with solitary renal masses. Two
of them had 9 cm tumours and HIFU was applied just as marker lesion before
radical laparoscopic nephrectomy; the rest had SRM with a median size of 22 mm
and were treated with a “curative intent” applying HIFU to the entire tumour
with a margin of 2-3 mm of
surrounding parenchyma. Seven of these tumours were operated afterwards by
means of a laparoscopic partial nephrectomy and one was left in situ in a
patient with high comorbidities. In the SRM subgroup, a median HIFU exposure
time of 19 minutes (range 8–42) was used. The
first two patients showed, in the subsequent pathological examination, just a 2-3 mm of vital
tissue adjacent to where the HIFU probe was approximated with the rest of the
tumour with thermal necrosis; the authors explained this phenomenon to an
excessive cooling of the probe, and changing this parameter, they did not
observe it again in the remaining cases, although a patient showed a 20% central area with no
thermal effects, showing complete thermal necrosis in the 4 remaining removed cases
(57%). The nonexcised tumour
was successfully treated attending to real-time US
data,
examination of core biopsies showing thermal necrosis, and follow-up CT scans
up to 6 months showing no constraint
enhancement and shrinking of the lesion [15].


## 4.4. Complications

There have
been just two severe complications due to HIFU application in the abdominal
cavity in humans: a superior mesenteric artery infarction and a perforation of
the terminal ileum, but both were after treatment of recurrent or metastatic
colon carcinoma [29]. When focused to kidneys, no serious side effects have
been shown [27]; just 2 patients had grade III skin lesions [28], but the most
common type of skin toxicity is less than 1cm blister or track at the treatment
site [17]. Changes in laboratory tests are also nonsignificant
[17, 18].


## 5. Discussion

Technology has improved the
initial problems of the first HIFU intents to treat kidneys with devices
derived from piezoelectric lithotripters [22] which could not focus the targeted
lesion; the development of a new HIFU source (Storz UTT System, Storz Medical
AG, Kreuzlingen, Switzerland) with a smaller (10 cm) diameter for flexible
extracorporeal application permitted the authors to focus precisely on the
targeted area in an ex vivo scenario with perfused kidneys, adjusting the pulse
duration and the power of the generator to the lesion size [30].One of the major
problems with HIFU is that from an extracorporeal application, there are
several factors that interfere between the power emitted by the ultrasound
probe and the energy arriving to the targeted area: focal length, type, and
characteristics of the tissue to be crossed through variable vascularization of the kidney and
its mobility as well as
the limitation proximity of air (gut) or bone (ribs) because of
reverberation, acoustic shadowing, and refraction [31], the last with burning
power with potential damage to close organs.Another drawback of percutaneous
HIFU application is the absence of a reliable radiologic method controlling the
effects of HIFU in real time. Research is being done to find more fixed devices
coupled with respiratory movements trying to save absorption of ultrasound
energy from nontargeted tissues like ribs, fat, or muscles; MRI is being more
extensively proposed as a guide to the treatment compared with regular
ultrasound due to its information regarding temperature changes in the treated
tissue within seconds after application [31]. Unfortunately, movement of the
kidney also affects the accuracy of MRI thermometry [32]. Mobility has been
partly corrected using multichannel focused US
systems, trying to combine
motion tracking and feedback electronic steering of the HIFU beam [33] and
multiprobe systems of small-aperture confocal HIFU transducers
that also theoretically
permit more flexible targeting [34, 35].All these reasons could explain the
poor results in the clinical setting, mostly when histopathological assessment
of thermal necrosis on the targeted tissue has been studied. The limited
clinical experience with the extracorporeal approach and its poor results make
this approach not suitable to treat renal cancer in humans, and it has to be
considered a technique under experimental research [12].Although percutaneous approach would
be the ideal and real “no invasive,” laparoscopic approach facilitates
resolutions of many of the problems facing the percutaneous approach. The use of
the 18 mm laparoscopic HIFU transducer, applicable to conventional lap
armamentarium and controlled by US, as shown by Klingler et al. in phase I study, indicated
just for peripheral tumours not larger than 3.5 cm in size [15], opens a window
to clinical research with this method as it really does not clamp the kidney or
puncture it as other ablative techniques. Although the protocol is under
evolution, the authors have shown safe and promising results with at least
better thermal necrosis results than those obtained with the percutaneous approach, but it has to be
kept in mind that laparoscopy itself is not complication-free as it needs
general anaesthesia, pneumoperitoneum, and tumour isolation, so this approach
will have to be compared in randomized trials with other nonablative techniques
and also with watchful waiting policies in front of SRM in elderly or unfit patients,
the subgroup of patients where it makes sense to avoid open or laparoscopic
partial nephrectomy for an SRM.The follow-up of SRM treated with
HIFU is generally performed by contrast-enhanced CT and MRI, but other methods
such as PET and microbubble contrast-enhanced ultrasound are under evaluation [36].
Microbubbles increased the ablation efficiency and the visibility of tissue
destruction attending to the appearance of hyperechoic regions within the
targeted tissue [6]. As with the rest of the nonablative techniques, definitive
follow-up protocols are missing [37], and the role of the biopsy in contrast-enhanced
lesions has to be investigated [38].One of the advantages
of HIFU applications is that treatments could be repeated, but the need to do
it under general anaesthesia results in a limitation of this strategy.Vast research is needed
to establish standards of pulse and power levels which ascertain tissue death,
as well as the number and types of probes utilized, as in ex vivo porcine experiments, at
identical power levels, lesions induced by multiple probes were larger than
those induced by single probe [34]. Another nonresolved issue is the final
extent of the coagulative thermal-induced necrosis with time. Finally,
extracorporeal or laparoscopic approach will have to define their advantages.Thus, to establish the clinical
usefulness of HIFU to treat SRM, long-term follow-up studies are needed taking
into account recurrence-free survival data, quality of life parameters,
complications and cost analysis, and all these data compared in clinical trials
with open or laparoscopic partial nephrectomy as gold standard techniques [39],
cryotherapy and radiofrequency as minimally invasive more developed techniques [40],
and watchful waiting policy [3] as options to manage small renal masses.


## 6. Conclusions

HIFU is a promising
approach to treat SRM because it is probably the most minimally invasive among
the proposed techniques. Nevertheless, the number of treated patients is very
small, and its results with the percutaneous approach make it not applicable to
the humans with a curative intent. Laparoscopic approach makes it a loose part
of its “minimally invasive” principles, but preliminary data show better
thermal necrosis results and better US real-time control of the treatment.  For the moment, we think that HIFU has to be
considered as an investigational technique. Technical improvements could certainly
facilitate its use in the management of SRM in the near future.



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