, Tonolini, and Cova are with the Department of Radiology,
General Hospital, Busto Arsizio, Italy.
Currently, percutaneous radiofrequency (RF) ablation is widely
employed for minimally invasive treatment of primary and metastatic
liver tumors. Its safety and effectiveness have been demonstrated
in several large studies and its advantages include lower morbidity
and mortality compared with surgical resection, the possibility of
repeated treatment sessions if local recurrence or new lesions
develop, and markedly reduced treatment costs and hospital stays.
The results of RF ablation for both hepatocellular carcinoma and
liver metastases compare favorably with those reported in recent
surgical series, although patients are not usually candidates for
Recent technical improvements including internally cooled
pulsed current application,
and peritumoral saline injection prior to energy deposition
were developed in order to increase the extent of induced
coagulation and, therefore, to allow the treatment of larger
Thermal ablative therapies destroy neoplastic lesions.
Coagulation necrosis is achieved through a mechanism of protein
denaturation and irreversible inactivation of cellular and
mitochondrial enzymes and of nucleic acid-histone complexes. The
treatment of hepatocellular carcinoma (HCC) in a cirrhotic liver
using RF ablation benefits from the "oven effect": the surrounding,
densely fibrotic, and poorly vascularized liver tissue and the
fibrous capsule hinder thermal conduction away from the target
lesion, and thus maintain optimal heat diffusion in the softer,
usually well-circumscribed tumoral nodule.
Conversely, liver metastases are not encapsulated and tend to
infiltrate the surrounding, well-vascularized liver that can act as
a heat sink to limit tissue heating.
Therefore RF ablation should aim to necrotize not only the
metastatic nodule, but also a 0.5 to 1.0 cm thick rim (ie, a
surgical "safety margin") of surrounding liver tissue in order to
kill infiltrating tumor undetectable by currently available imaging
methods and reduce risk of recurrence.
Diagnostic imaging is of paramount importance in all of the four
steps of tumor ablation: 1) detection of lesions and selection of
patients for treatment; 2) targeting of lesion(s) with optimal
positioning of the energy applicator; 3) immediate assessment of
therapeutic result; and 4) long-term follow-up. In our experience,
the use of contrast-enhanced ultrasound (CEUS) represents a
significant improvement in each of these steps and may optimize
patients' management and treatment results.
Herewith we report our experience with the use of a
second-generation ultrasound (US) contrast agent (SonoVue
sulphur hexafluoride, Bracco, Milan, Italy) and low mechanical
index (MI) (or low acoustic pressure) continuous-mode ultrasound,
employing a new imaging technique (Contrast Pulse Sequencing [CPS],
Acuson/Siemens, Mountain View, CA). Since it has been demonstrated
that the detectability of contrast agents at low MIs can be
improved by processing received nonlinear energy that exists in the
same frequency band as the transmitted signal, CPS processes
signals from multiple transmit pulses to extract nonlinearly
generated signals in the fundamental frequency. This can improve
sensitivity and specificity to contrast agents compared to second
harmonic imaging techniques.
Detection of Lesions and Selection of Patients
Early detection and accurate assessment of the extent of
neoplastic liver disease at the time of diagnosis or during the
course of treatment is crucial to optimal patient management and
may result in prolonged survival and improved chance for cure.
Patients with chronic liver disease/cirrhosis may be treated with
RF ablation for up to 4 to 5 HCC and/or dysplastic lesions, in
absence of portal thrombosis and liver function decompensation.
Patients with previously treated colorectal or other primary tumors
may undergo RF ablation of 1 to 4 metachronous liver metastases,
each smaller than 4 cm.
Multiphasic contrast-enhanced helical computed tomography (CT)
and dynamic gadolinium-enhanced magnetic resonance imaging (MRI)
provide convenient staging of hepatic and extrahepatic neoplastic
involvement. Conventional ultrasound, which represents the most
widely available low-cost imaging modality for the screening of
liver disease, is less accurate than CT and MRI for the detection
of focal lesions, particularly of smaller ones (<1 cm).
In our preliminary experience, CEUS with SonoVue and CPS further
improved the results achieved with a first-generation contrast
agent and color-power Doppler
and with low-MI harmonic imaging.
In the first 3 patients, conventional doses of 2.4 or 4.8 mL of
SonoVue were administered in rapid bolus injection, followed by a
3- to 5-mL saline flush. For the remaining 6 patients,
progressively decreasing doses of SonoVue (up to 0.6 to 1.2 mL)
were given and no significant impairment of image quality and
sensitivity was found. The whole vascular phase was studied in all
patients, consisting of arterial (15 to 25 sec following the
injection, with some delay in cirrhotic patients), early portal (45
to 60 sec) and full portal phase (90 to 240 sec).
For local staging of both primary and metastatic liver cancer,
CEUS with CPS demonstrated sensitivity rates equal to that of
helical CT in 7 (77.8 %) of 9 cases and in the remaining 2 (22.2%)
cases, it was superior to helical CT, particularly for
infracentimetric lesions (Figure 1).
During pretreatment CEUS, images and/or movie clips were stored
digitally in order to "map" the lesions to be targeted during the
operating session and to compare pretreatment findings with
posttreatment enhanced images.
RF Procedure and Targeting of Lesions
Although ultrasound represents the modality of choice for
guiding ablative procedures, inherent limitations of conventional
US (related to small size, poor conspicuity, and inhomogeneity of
liver parenchyma) may hinder the targeting of focal tumors. In
these occurrences, CEUS with CPS is repeated in the interventional
room after inducing anesthesia and the electrode is inserted during
the vascular phase in which the maximum lesion conspicuity is
achieved, eg, in the arterial phase for hypervascular lesions such
as HCC and in the portal phase for hypovascular metastases. In our
experience with CPS, 11 malignancies in 6 patients were punctured
during the vascular phases, with 100% targeting accuracy.
All the 17 malignancies were treated using RF ablation: either
single or clustered 17G cool-tip ablation electrodes connected to
an RF generator (CC1, Radionics, Burlington, MA) were inserted into
the targets percutaneously, under general anesthesia for 12 to 24
Assessment of Therapeutic Response
Whereas most RF ablation series report a high rate of apparently
complete tumor necrosis on initial postablation evaluation, a
moderate rate of local recurrences probably resulting from a lack
of radicality may occur.
Achieving only partial necrosis implies the need to perform
retreatments with increased costs, patient discomfort, greater
technical difficulties, and a higher rate of failure.
When the first RF treatment has not eradicated the tumor
effectively, it is extremely difficult to differentiate active
tumor from coagulation necrosis, and therefore to target residual
Ultrasound provides real-time guidance of ablation treatments,
but sonographic and color/power Doppler findings observed during
the ablation procedure provide only a gross estimate of the extent
of induced coagulation necrosis and, therefore, are not useful to
reliably assess the completeness of the treatment. Furthermore,
additional repositioning of the RF electrode may become obscured
because during the application of thermal energy a progressively
increasing hyperechogenic "cloud" due to gas microbubble formation
and tissue vaporization appears for 5 to 8 minutes around the
distal probe. The most important imaging finding that suggests
complete treatment of a focal liver tumor is the disappearance of
any previously visualized vascular enhancement on contrast-enhanced
This assessment is usually achieved using either biphasic helical
CT or dynamic gadolinium-enhanced MRI. Radiologic-pathologic
correlation studies demonstrated that both modalities can predict
the extent of coagulation area to within 2 to 3 mm.
The lack of neoplastic or parenchymal contrast enhancement in
any vascular phase throughout the entire lesion is the hallmark of
complete ablation. This evaluation is easily feasible for
hypervascular HCCs, whereas for hypovascular metastases the
confident assessment of complete ablation can only be inferred
based upon the necrosis volume exceeding the original lesion and a
0.5 to 1 cm "safety margin" in every diameter. Unfortunately,
neither CT nor MRI can be performed during the ablative procedures
under general anesthesia, unless treatment is performed under CT or
First-generation contrast agents with color Doppler and power
and, more recently, with pulse inversion sonography
have been used successfully to evaluate the therapeutic response to
ablative treatments, demonstrating the capability to detect
persistently perfused tissue consistent with residual viable tumor,
with a reported accuracy for detection of incompletely ablated
areas ranging from 75% to 82%.
Our preliminary experience with CPS and SonoVue was even more
encouraging. In 9 patients, 17 liver malignancies (9 metastases
from colorectal cancer and 8 primary liver tumors) ranging in size
from 1.0 to 3.9 cm, preliminarly studied with CPS and SonoVue,
underwent immediate postablation evaluation using the same
modality, 5 to 10 minutes after the assumed completion of the RF
session, with the patient still under general anesthesia.
Comparison of immediate postablation images with stored
pre-ablation scans was performed in all cases.
For 15 of the 17 lesions, no residual enhancement was
demonstrated either inside the or at the periphery of the tumors
(Figures 1 and 2). These lesions did not undergo further treatment
and CT scans performed the following day confirmed the complete
treatment in all 15 tumors. No immediate CEUS-guided targeted
retreatment was needed. In the remaining 2 malignancies, no
residual enhancement was found with CEUS, but the following CT scan
depicted few tiny intralesional enhancing areas suggesting local
Based on our experience, CEUS with CPS and a second-generation
US contrast agent is extremely accurate for the detection, local
staging, CEUS-guided ablation, and immediate assessment of the
therapeutic results. This simplifies patient management and reduces
costs by decreasing the number of RF procedures and follow-up