Download Role of CEUS (Contrast-Enhanced Ultrasound) in the differentiation

Role of CEUS (Contrast-Enhanced Ultrasound) in the differentiation between benign and
malignant breast masses
Keywords
Breast, breast neoplasm, contrast media, sulfur hexafluoride, ultrasonography
1
Introduction
Contrast enhanced ultrasonography (CEUS), a new ultrasonography technique, was
introduced in the late 90s and has recently gained interest in various fields of mass evaluation.
CEUS is based on the angiogenesis and vascularization of masses that are strongly related
with tumor growth, invasion and metastasis (1). It has been thought that the vascular and
microvascular information of the masses play an important role in the distinction between
benign and malignant masses and non-invasive modalities, such as color and power Doppler
US and breast MRI have been used for the evaluation of mass vasculature. However, the
results of vascular assessment of color and power using Doppler US remain controversial (2,
3).
This contrast specific imaging technique, in conjunction with the development of
ultrasonography contrast agents, has improved the detection of characteristic vascular
morphological features in several organs. It has proved useful in the evaluation of focal liver
lesions that are too small to detect with other modalities, such as computed tomography (CT)
and MRI (4). In the case of the breast, studies regarding the quality of CEUS evaluation are
relatively rare and initial results were disappointing as the microbubbles are fragile when
used with high frequency US (5).
In contrast, the development of a second-generation contrast agent (microbubble based
contrast agent) and dedicated new software that is available for high frequency transducer
allows better quantitative analysis and opened new prospects in the breast.
The aim of this study was to evaluate the usefulness of CEUS to distinguish between benign
and malignant breast masses using enhancement pattern and perfusion kinetics parameters.
2
Material and methods
The Institutional Review Board of our hospital approved this study design and protocol and
all patients gave informed consent prior to examination. A total of 20 female patients (mean
age 52.6 years, range 33-77 years) who underwent grey scale ultrasonography and were
verified as having breast masses were selected to undergo CEUS. The inclusion criterion was
the presence of masses on grey scale US with masses larger than 0.5cm in size. The exclusion
criteria were contraindications to contrast agent administration, patients with cardiovascular
or pulmonary diseases, or those pregnant or breast feeding.
1. Study design
Both conventional grey scale ultrasonography and CEUS were performed using iU22
(Philips Healthcare, Bothell, WA) equipped with a 12-5 MHz linear array transducer and
special modalities Sono CT (real-time compound imaging scanning, crossbeam scanning) and
XRES ( speckle, noise and clutter reduction imaging).
A second generation contrast agent (Sonovue®, Bracco, Millan, Italy), which is a pyrogenfree lyophilized powder consisting of phospholipid microbubbles containing sulfur
hexafluoride gas with a mean diameter of 2.5 µm, was used. Intravenous bolus injection of
4.8mL Sonovue via 20 gauge cannula in the left antecubital vein, followed by a flush with 10
mL of normal saline solution was carried out. The probe was positioned on a target mass and
real time imaging was recorded continuously as a video clip for up to 3 minutes, immediately
after the injection. All recorded images were stored in the iU22 system and were then
exported to a personal computer.
2. Image analysis
All conventional and CEUS studies were performed by a single breast radiologist (HY Oh, 7
years of experience in breast imaging). The imaging files were reviewed by 2 radiologists.
They retrospectively analyzed enhancement pattern as no, homogenous, peripheral or
heterogeneous enhancement.
Vuebox® (Bracco Suisse SA), a new quantification software was used to evaluate perfusion
kinetics of the breast masses. The settings were as follows: the mechanical index (MI) was
less than 0.1; dynamic range 40; frame rate 15 frames per second; the image depth was 3 or
4cm; the single focus was at the bottom of the image; the prove was stabilized manually; and
no pressure was exerted. The observed indexes included were the RT (Rise time), the PE
(Peak enhancement) and the WiR (Wash in rate). They were obtained by locating a region of
interest (ROI) of the richest vasculature portion of the breast mass and another ROI was
located on the normal breast parenchymal tissue for reference.
3. Statistical analysis
Statistical analysis was carried out using the SPSS package (version 22.0, IBM Corporation,
Chicago, IL, USA). For the evaluation of the enhancement pattern, we used the chi-squared
test to determine the statistical significance. The kinetic curves were automatically obtained
when using the Vuebox® software.
The student’s t-test was used to determine which of the kinetic parameters were significantly
different between the benign and malignant masses. The mean values and standard deviations
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were given for all of the kinetic parameters. We also used box-and-whisker plots for each
kinetic parameter to identify the graphical differences in both benign and malignant groups.
Statistical significance was established as a P value of <0.05.
4
Results
All lesions evaluated were successfully identified on both grey scale US and CEUS and
ranged between 0.8-3.7cm in size (mean 2.0cm).
1. Histopathologic findings
Pathological diagnosis was available for all masses as all of them underwent breast
biopsy after CEUS. Of the 20 lesions, 14 (70%) were confirmed as malignant by
histology. The most common diagnosis was invasive ductal carcinoma, which was
found in 11 of the 14 cancer cases and one of them was recurrent IDC which occurred
5 years after the first surgery. Other diagnoses included intraductal papillary
carcinoma (2/14) and invasive lobular carcinoma (1/14). The remaining 6 (30%) of
the total 20 lesions were benign and included fibroadenoma (5/6) and duct ectasia
(1/6).
2. Enhancement pattern
The results of CEUS enhancement patterns are described in Table 1. There were no
significant differences between the malignant and benign masses in all enhancing patterns (P
value <0.05). The most common malignant enhancement pattern was heterogeneous
enhancement (7/14) followed by peripheral enhancement (4/14). A total of 4 malignant
masses and 2 benign masses have shown peripheral enhancement in this study and the
histology of 2 benign masses were fibroadenomas (1.3cm, 1.5cm) (Figure 1).
One of the heterogeneously enhancing mass has shown interesting enhancement pattern.
Among the solid portion of the mass, some areas showed contrast enhancement while some
areas did not. (Figure 2).
3. Kinetic parameters
Among the 3 kinetic parameters used in this study, a significant difference was only found
between the benign and malignant lesions in the PE (malignant 21.1 ± 17.0, benign 7.1 ± 5.8;
P value <0.05). There was no significant difference in the RT (P value = 0.76) and the WiR
(P value = 0.12). Even though the P value of the RT and the WiR have shown no significance,
the box and whisker plots of these 2 parameters have shown some differences in distribution
(Figure 3).
The results of perfusion kinetic parameters were summarized in Table 2 and the kinetic
curves were automatically obtained as the data was analyzed using Vuebox® software.
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Discussion
Recently, the clinical applications of CEUS have greatly increased in the field of breast
evaluation. It is mainly used in the differentiation of benign and malignant masses and most
studies have agreed on the particularly fast contrast enhancement with more intense
enhancement and fast washout in malignant lesions, compared with benign (6, 7). The kinetic
features of CEUS have often been compared with kinetic features of contrast enhanced MRI
(CE-MRI), which has been the main modality of evaluation of tumor vascularization to date.
Ricci et al. compared the result of CEUS with the results of MRI, and show good correlation
between results (8). However, as compared with CEUS, CE-MRI is more expansive and
uncomfortable during the examination since it takes longer with the patient in the prone
position.
In this study, we used a new quantitative software named Vuebox® that provides perfusion
kinetic parameters, as well as the kinetic curve. Among 2 modes of injecting contrast agent
(bolus and continuous) since bolus injection is the standard method of injecting for noncardiac indications, we used the bolus injection with single intravenous injection and for the
dose, as Saracco et al. have determined, we used 4.8mL of contrast agent, rather than 2.4 or
1.2mL, for the better image quality (9). None of the patients have shown any complications
following contrast administration and, using the datasets, we examined both the perfusion
kinetic parameters and CEUS enhancement patterns.
In evaluation of the perfusion kinetic patterns, the parameters were divided into 3 categories:
those representing an amplitude, a time and a combination of amplitude and time. We
evaluated the PE (peak enhancement) as the amplitude related parameter, RT (rise time) as
the time related parameter and the WiR (wash in rate) as the perfusion parameters in a
combination of amplitude and time. Among these parameters, in agreement with the study
done by Caproni et al., in which a significantly higher PE was noted in malignant mass (28.9%
± 13.6) compared with benign mass (18% ± 8.5), only the PE was noted as significantly
different in differentiating between the benign and malignant masses (21.1 ± 17.0 for
malignant, 7.1 ± 5.8 for benign) (10). We believe it was strongly associated with the
angiogenetic process where malignant tumor vascular morphology and distribution are
obviously different from benign masses. The P value of the RT and the WiR have shown no
significance. However, the box and whisker plots of these 2 parameters have shown some
differences in distribution. This may be due to the small sample size of this study and if a
larger population is included, then statically significant differences may be identified.
The CEUS enhancement patterns were classified as no, peripheral, homogenous or
heterogeneous enhancement in the present study. There were no standard methods of
classifying the enhancement pattern, therefore most of the authors used their own
classification and some of them correlated the findings with the histopathological features. In
most previous studies, the peripheral enhancement of the mass was the most specific sign of
malignancy and this event is probably due to the fact that tumor vessels are present more on
peripheral portion rather than central portion of the mass (5, 11). In this study, 2 benign
masses which were pathologically proven as fibroadenomas, have shown peripheral
enhancement. This shows the presence of the peripheral enhancement not always indicated
malignancy and Liu also noted that this pattern was seen in the benign condition,
granulomatous mastitis (5)
6
An interesting case was noted in a heterogeneously enhancing mass. Among the solid
portion of the mass, some areas showed contrast enhancement while some areas did not. We
found it interesting and considered this may help us when performing biopsy of the
pathological confirmation, providing us with the information about which portion is preferred
for biopsy.
The present study has several limitations. Firstly, our study included a small number of
patients and therefore requires further investigation with a larger number of patients to be
confident about the result of this study. Secondly, the injection of contrast agent was done on
the left sided arm regardless of the position of breast masses on right or left. This may have
influenced the perfusion kinetics. Thirdly, only the pathologically proven benign masses were
included and typical probable benign masses from US that need 2 yearly follow-up (BIRADS
category 3) and BIRADS category 2 masses were not included. This may have led to bias in
the interpretation of lesions by the radiologists.
In conclusion, among the perfusion kinetic parameters, the PE was useful in distinguishing
benign and malignant masses and none of the enhancing patterns were significant. However,
it seems CEUS may be helpful in biopsy, particularly to identify the part of the mass to be
biopsied. Further evaluation with a larger population is required to confirm the results of our
study.
Acknowlegement
This study was supported by 2014 Research Grant from Kangwon National University
( No. 120140658)
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Table 1. Enhancement patterns of breast masses
No enhancement
Homogenous
Peripheral
Heterogeneous
Malignant (n=14)
2
1
4
7
Benign (n=6)
2
1
2
1
9
Table 2. Perfusion kinetic parameters of breast masses
Malignant
RT
20.5 ± 9.2
PE
21.1 ± 17.0
WiR
1.8 ± 1.3
Note: For all coefficients, P <0.05
Benign
18.7 ± 16.5
7.1 ± 5.8
0.8 ± 0.8
RT: Raise time, PE: Peak enhancement, WiR: Wash in rate
10
P value
0.76
0.02
0.12
Figure 1. CEUS images of a fibroadenoma showing peipheral enhancement.
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Figure 2. A 76 year old woman with intraductal papillary carcinoma.
(A) CEUS shows a heterogenous enhancement pattern. The green circle indicates the
heterogeneous enhancing portion of the mass and blue circle indicates the solid portion of
the mass which did not show contrast enhancement. The yellow circle indicates normal
breast parenchymal tissue.
(B) Time intensity curve generated by Vuebox® software showing fast contrast
enhancement and washout.
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Figure 3. Boxplots comparing RT(A), PE(B) and WiR(C) between benign and malignant
breast masses. RT: Raise time, PE: Peak enhancement, WiR: Wash in rate
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