Introduction
Hepatic metastasis is a major problem in breast cancer patients. The detection of these lesions has treatment and prognostic implications, and accurate staging is also a prerequisite for monitoring chemotherapy. Although an abdominal liver ultrasound is not recommended for routine breast cancer surveillance, as to other conventional examinations, ultrasonography has been reported as effective for the “early” detection of hepatic recurrences [
1,
2]. Despite the recent development of new techniques, including 18-fluro-2-deoxyglucose (FDG) positron emission tomography (PET) computed tomography (CT) and dynamic magnetic resonance imaging (MRI), for the detection of hepatic metastasis from breast cancer, the use of ultrasonography (US) for the assessment and follow-up of hepatic metastatic disease might benefit from a reliable, easily available, low cost, noninvasive imaging modality. Although B-mode US is commonly performed as a screening examination, most of the conventional US techniques have relatively poor sensitivity and specificity for imaging liver metastases (53–76 %), and trans-abdominal US is inferior in sensitivity for liver metastases compared with CT or MRI primarily reflecting a lack of contrast agents. Currently CECT and MRI are the only imaging modalities that offer the highest diagnostic potential for the assessment of liver metastases in breast cancer patients [
3,
4].
Contrast-enhanced US has been demonstrated as a suitable technique for the detection of hepatic malignancy or metastases and is more accurate compared with conventional B-mode US [
5‐
9]. However, the efficacy of contrast-enhanced US for the detection of hepatic metastases from breast cancer has not been specifically evaluated. Sonazoid (Diichi-Sankyo, Tokyo, Japan) is a new microbubble agent that provides a parenchyma-specific contrast image based on its accumulation in the Kupffer cells of the liver [
10‐
14]. Sonazoid has previously been approved for clinical use in Japan, and this agent presents a image in the post-vascular phase (Kupffer image) with a long duration, followed by the images of the arterial phase and the portal phase (vascular phase) [
15,
16]. In the present clinical study, we demonstrate the use of Sonazoid in contrast-enhanced US for the detection of hepatic metastasis in patients with breast cancer.
Discussion
In the present study, we demonstrated that liver metastasis from breast cancer frequently shows hypoechoic defects under contrast Sonazoid-enhanced US compared with the surrounding normal liver parenchyma enhanced through increased echogenicity resulting from treatment with a Sonazoid microbubble contrast enhancer (Fig.
1).
Small liver metastases from breast cancer were only detected through contrast Sonazoid-enhanced US, and conventional US did not show abnormality in metastatic lesions ranging from 4 to 17 mm in diameter. Similarly, CECT did not detect micrometastatic lesions of less than 13 mm in diameter. In contrast, SEUS at the post-vascular phase (Kupffer imaging) revealed 4–17 mm rounded small hepatic metastatic lesions (Figs.
3 and
4), compared with CECT scan showed a low sensitivity for detection and characterization of lesions smaller than 1 cm [
17]; contrast-enhanced US had detected small hepatic metastatic lesions (<1 cm) with a high sensitivity [
18]; and in this study, four additional small lesions had been revealed by SEUS, but not by CECT. These results suggest SEUS has better contrast resolution than CECT for detecting small hepatic metastatic lesions, and SEUS may improve the detection of miliary metastases (0.5–1 cm) [
19].
The detection of large liver metastases from breast cancer using conventional B-mode US and SEUS in the post-vascular phase, revealed that 82.3 % of most enhanced lesions showed reduced enhancement (defect/washout) (Fig.
5), and 17.7 % of the lesions showed hypoechoic changes with rim enhancement in the post-vascular phase using SEUS, which was not visible through baseline ultrasound (Fig.
6).
In the present study, contrast Sonazoid-enhanced US showed higher sensitivity and accuracy for the detection of liver metastases from breast cancer compared with conventional unenhanced B-mode US. Several clinical trials involving contrast-enhanced US using Sonazoid to detect hepatic metastasis have been performed worldwide in various cancers [
9,
20‐
22] and these previous studies have also demonstrated the improvement in accuracy of contrast-enhanced US in diagnosing hepatic metastasis [
23‐
25]. Differential diagnosis of hepatic metastasis between breast cancer and other original cancer may indeed be a problem, there were some reports demonstrating that hepatic cellular carcinoma shows increased enhancement in the arterial phase, metastasis from gastrointestinal cancer and neuroendocrine tumor can be identified with the hypoenhancement in the portal venous and the post-vascular phase [
22]. However, as far as we know, no published study has specifically reported the value of SEUS for detecting hepatic liver metastases from breast cancers.
Contrast-enhanced ultrasound with Sonazoid detected significantly more metastases compared with conventional US, with a sensitivity of 98.8 versus 66.7 %. However, SEUS revealed no additional patients with metastatic disease. The hepatic metastases detected through SEUS were indeed relatively small lesions (4–17 mm), often associated with larger lesions. The detection of hepatic metastases from breast cancer using conventional US is limited by the relatively small difference in background patterns between the lesions and hepatic parenchyma, resulting in poor contrast differentiation between the two tissues, likely reflecting the difficulty in definitively diagnosing liver hemangioma and focal fatty change/sparing lesions using only B-mode US. The use of an ultrasound contrast agent such as Sonazoid increases the echogenicity of the liver at the post-vascular specific phase as the microbubbles accumulate in the normal parenchyma.
Although we did not specifically compare the value of the different vascular phases in the detection of metastases from breast and other cancers, the post-vascular phase image (Kupffer image) was valuable, as 83.3 % of the metastases from breast cancer were perfusion defects in the parenchyma, and 17.7 % of breast cancer metastases was iso- or hypoechoic compared with liver parenchyma, showing hypoechoic changes with rim enhancement in the post-vascular phase. However, we did not confirm this finding quantitatively because only 14 of the 79 lesions detected showed central necrotic hypoechoic changes. Notably, the internal content of the metastatic lesions or the areas showing necrotic changes were also correctly identified using SEUS. Because the data from the 19 patients subjected to CECT was limited, the difference between SEUS and CECT scan imaging was not significant in this study. Four lesions were missed by dynamic CT scan examination, but these lesions were identified using SEUS, likely reflecting the small size of the lesion. However, one patient, who showed false-negative results after both baseline B-mode and SEUS, had a subdiaphragmatic lesion that was not accessible to sonography. The limitations of dynamic CT scanning make it difficult to detect small metastases, and the limitations of US make it difficult to visualize subdiaphragmatic lesions.
Furthermore, ultrasound contrast agents, including Sonazoid modify the basic physical interactions between ultrasound waves and hepatic tissues and amplify the signal produced by flowing blood. Thus, Sonazoid might be useful for detecting subtle flow abnormalities and distinguishing areas of abnormal flow relative to normal background parenchymal perfusion. As a result, these contrast agents might improve the characterization of focal liver lesions compared with standard B-mode US, while providing complementary information with other imaging modalities [
26‐
28]. In the present study, we also demonstrated using contrast Sonazoid-enhanced US for the adequate detection of benign lesions, including three hepatic hemangiomas and two focal fatty changes, in patients with metastatic breast cancer.
Thus, these results suggest that SEUS, followed by conventional B-mode US for evaluating breast cancer metastases, might not only be used to successfully detect malignant lesions with higher sensitivity and accuracy, but also to identify benign lesions, including hepatic hemangioma or focal fatty changes, for the differential diagnosis of hepatic lesions. Moreover, because it is competitive, cost effective and less invasive, SEUS technique used for follow-up of hepatic metastases from breast cancer may be an alternative to other imaging modalities including CT scan and MRI. Consequently, the development of a new SEUS approach could improve the diagnostic sensitivity and detection accuracy for hepatic breast cancer metastases and could also provide important information for making treatment decisions for patients with breast cancer.
These results were presented at the 72nd Annual Meeting of the Japanese Breast Cancer Society in June 2013.