Abstract
Microwave ablation has been utilized clinically as an alternative to surgical resection. However, lack of real-time imaging to assess treated regions may compromise treatment outcomes. We previously introduced electrode displacement elastography (EDE) for strain imaging and verified its feasibility in-vivo on porcine animal models. In this study, we evaluated EDE on 44 patients diagnosed with hepatocellular carcinoma, treated using microwave ablation. The ablated region was identified on EDE images for 40 of the 44 patients. Ablation areas with EDE were 13.38 ± 4.99 cm2, when compared to 7.61 ± 3.21 cm2 on B-mode imaging. Contrast and contrast to noise ratios obtained with EDE was on the order of 232% and 98%, respectively, significantly higher than values measured from B mode images (p <0.001). This study shows that EDE is feasible in patients and provides improved visualization of the ablation zone when compared with B-mode ultrasound.
Keywords: Ablation, Elastography, Elasticity Imaging, Microwave ablation, HCC, Strain imaging
Introduction
Hepatocellular carcinoma (HCC) is the 6th most common cancer and 3rd leading cause of cancer related mortality worldwide (Lencioni and Crocetti 2012). Surgical resection of liver tissue is the standard procedure for the cure of HCC although there are critical constraints for its wide-spread use. The following criteria have to be met for successful surgical resection: (1) the cancer is limited to a single liver lobe; (2) liver function is well preserved; and (3) the patient neither has abnormal bilirubin nor portal hypertension (Lencioni and Crocetti 2007). However, cirrhosis commonly occurs with HCC, and only up to 5% of cirrhotic patients with HCC fit the constraints described above for liver resection (Lencioni and Crocetti 2007). Therefore, as few as 9% of patients with HCC are suitable candidates for surgical resection (Liang and Wang 2007). With the development of minimally invasive treatments such as percutaneous radiofrequency ablation (RFA) and microwave ablation (MWA), thermal ablation has been adopted as the primary treatment option for HCC, especially for early stage interventions (tumor sizes < 3 cm) (Lencioni and Crocetti 2012; Shiina et al. 2012). Existing clinical studies have shown that treatment outcomes with ablation procedures are superior or at least equivalent to surgical resection or ethanol injection for these early stage HCC tumors (Lu et al. 2005; Lencioni and Crocetti 2007; Liang and Wang 2007; Lencioni and Crocetti 2012; Maluccio and Covey 2012; Shiina et al. 2012).
MWA, introduced as an ablation technique initially in Japan (Murakami et al. 1995), has now been increasingly applied worldwide (Shibata et al. 2002; Lu et al. 2005; Liang and Wang 2007; Maluccio and Covey 2012; Qian et al. 2012; Swan et al. 2013). Instead of generating the thermal dose by incorporating the patient as part of a closed loop circuit as in RFA, MWA emits microwave energy to agitate water molecules causing coagulation necrosis with a local impact. Thus, MWA delivers consistently higher intra-tumor temperatures, with reduced impact from blood flow in large vessels, enables faster ablation times, and provides an improved convection profile (Liang and Wang 2007; Lencioni and Crocetti 2012; Qian et al. 2012). Multiple probes can be applied simultaneously to create larger tumor ablation volumes (Harari et al. 2015). MWA therefore has several advantages over RFA including increased power, increased volume of direct heating, ablation consistency in different tissue types, and no requirement for ground pads (Lubner et al. 2013; Wells et al. 2015b; Ziemlewicz et al. 2016). With these technological advantages, MWA has been increasingly cited as the more commonly utilized percutaneous ablation method (Wells et al. 2015a; Ziemlewicz et al. 2015). Some investigators have reported that MWA does not show an obvious improvement over RFA in treatment outcomes (Shibata et al. 2002; Lu et al. 2005; Qian et al. 2012), however these studies utilized previous generation microwave technology. When evaluating current generation technology, MWA has shown a significantly lower rate of local tumor progression than RFA (Potretzke et al. 2016). The modality limitation might also be compensated by other treatment methods such as trans-arterial chemoembolization (TACE) to limit the blood supply from the hepatic artery to reduce the heat sink effect of large vessels (Liang and Wang 2007; Maluccio and Covey 2012). One recent study has shown that MWA could lead to satisfactory outcome even for tumor sizes greater than 3 cm which was previously considered to be the maximum suitable size for thermal ablation procedures (Ziemlewicz et al. 2015).
Ultrasound elastography has been considered as an alternative for ablation monitoring since the stiffness contrast between an ablated region and surrounding tissue is high (Righetti et al. 1999; Varghese et al. 2002; Varghese et al. 2003a; Bharat et al. 2005; Bharat et al. 2008b; Fahey et al. 2008; Kolokythas et al. 2008; Zhang et al. 2008; Rubert et al. 2010; Mariani et al. 2014; Zhou et al. 2014), and is not significantly impacted by the presence of gas bubbles (Varghese et al. 2004). Conventional, quasi-static ultrasound elastography is dependent on either an externally applied compression (Ophir et al. 1991) or internal physiological deformations (Varghese et al. 2003b; Varghese and Shi 2004; Shi and Varghese 2007) to produce displacements for estimating local tissue strain. The need for an external compressor would restrict the use of ultrasound elastography because it is cumbersome and generally cannot produce tissue displacements at sufficient depth. Acoustic radiation force (Sarvazyan et al. 1998; Nightingale et al. 2001; Fahey et al. 2008; Hoyt et al. 2008; Bing et al. 2011; Mariani et al. 2014), could be more suited for this task, but ARFI is limited by the small tissue displacements that can be generated (around 0.01 mm), and a relatively shallow imaging depth of around 8 cm. Beyond this depth the acoustic radiation force generated is too small to deform tissue due to attenuation of the signal (Zhao et al. 2011; Deng et al. 2015). The resulting data are also very sensitive to physiological motion such as cardiac pulsation and respiratory artifacts.
We previously introduced a novel, quasi-static ultrasound elastography technique, referred to as electrode displacement elastography (EDE) (Varghese et al. 2002; Bharat et al. 2008b; Rubert et al. 2010), designed specifically for monitoring percutaneous ablation procedures. Here the local tissue deformation for elastography is induced by manual perturbation of the ablation antenna (Varghese et al. 2002). In this study we investigated the feasibility of EDE in a clinical study done on 44 patients diagnosed with HCC and treated with MWA. The delineation of the ablated region on EDE images is compared with ablated region contours taken from conventional B mode images. Comparisons between the two modalities are made of the estimated ablation zone areas and of the detectability using contrast and contrast to noise ratio (CNR) features.
Materials and Methods
Patients and MWA system
Forty-four patients who underwent MWA for their HCC tumors were involved in this study. Informed consent to participate in this study was obtained prior to the ablation procedure under a protocol approved by the institutional review board (IRB) at the University of Wisconsin-Madison. Patients received MWA treatments under general anesthesia. Ultrasound radiofrequency data for EDE were acquired following antenna insertion, prior to onset of ablation, and immediately after the ablation procedure prior to the ablation antenna being removed from the insertion site. EDE images that exhibited clearly distinguishable ablation regions were obtained on 40 of the 44 patients. Four patients were excluded from analysis as the ablation zone could not be clearly delineated due to insufficient compression or excessive signal decorrelation artifacts.
MWA was delivered using a Neuwave Medical Certus 140 (Madison, WI, USA) operating at 2.45 GHz. Ablation duration and power were adjusted for each patient depending on the tumor size and location, with typical values of 5 min and 65 W, respectively. The MWA antenna was inserted under conventional ultrasound B mode imaging guidance in a CT imaging suite. In several patients multiple MWA antennae (maximum of 3, typically 2) were inserted at the same ablation site. MWA antenna position and placement within the ablation region were also confirmed using CT scans prior to the ablation procedure in cases where ultrasound B-mode imaging was not definitive. B-mode and EDE strain images were obtained after completion of the active ablation procedure, but prior to the complete dissipation of the gas bubbles to evaluate the post-treatment appearance.
EDE techniques and Strain image processing
The mechanical stimulus for EDE was induced by a physician by manually perturbing the ablation antenna. A small displacement (typically around 1 mm) was applied to the ablated region through the perturbation. No side effects such as additional bleeding or patient discomfort were noted as a result of the EDE procedure.
Loops of ultrasound radiofrequency data were recorded during the perturbation of the antenna. Data were acquired using a Siemens ACUSON S2000 system equipped with a curvilinear array transducer (6C1 HD) operating at a 4 MHz center frequency. Two frames of radiofrequency data were selected as “pre” and “post” deformation frames after reviewing the entire loop of images generated from the radiofrequency data. These data were then processed to estimate local tissue displacements. We selected frames such that the correlation coefficient between kernels did not drop below 0.75 at all depths to ensure that local displacements estimated are accurate (Chen and Varghese 2009). A two dimensional (2D) cross-correlation based tracking algorithm (Chen et al. 2009) was applied, where the cross-correlation kernel dimensions used were 3.5 wavelengths × 7 A lines. Assuming a sound speed of 1540 m/s and at a depth of 8 cm, the physical dimensions of the kernel were 1.35 mm × 3.29 mm along the axial and lateral direction, respectively. The kernel dimensions used are larger than those applied in breast elastography, where high frequency linear array transducers are used and kernel sizes of 0.385 mm (axial) × 0.507 mm (lateral) are applied (Xu et al. 2012). The larger kernel size was required in this study due to increased attenuation at deeper imaging locations, reducing the echo data signal-to-noise ratio, lower center frequency, and because of the smaller deformations introduced with EDE. Adjacent cross correlation kernels overlapped by 75% along the beam direction and one A-line in the lateral direction. Local displacement estimates were fit with a 15-point (0.375 μs, or 0.29 mm) linear, least squares fit, and the local strain values were computed as the gradient of the local displacements. EDE based strain images were generated offline on an Intel Core 2 Duo computer, with the tracking algorithm implemented using MATLAB (MathWorks, Inc. Natick, MA).
To account for the fan shaped geometry of data acquired using the curvilinear transducer, scan conversion was applied after displacement and strain estimations along the direction of the A-lines. A bi-linear interpolation was then applied to the strain values to calculate pixel values at scan converted positions on a rectangular grid.
Evaluation metrics for EDE vs. conventional B mode imaging
Area of the ablation region
Ablated zones are recognized in EDE because they exhibit lower strain than surrounding, untreated tissue. The estimated area of the ablation region was used as a feature to compare the 2D distribution of the low-strain zone on EDE and the hyperechoic region on B mode images. The ablation region was segmented manually on both sets of images. The area of the ablation region, S was calculated using:
(1) |
where Δ is the image pixel size and N is the number of pixels inside the segmented region.
Ablation region contrast
The contrast of the ablation region is defined as:
(2) |
where C represents the contrast, Io is the mean image pixel value of a rectangular region of interest (ROI) positioned within the ablated region, and Ib is the mean pixel value of a similar sized rectangular ROI adjacent to the ablated region.
For EDE, the ROI of the ablated region was defined within the dark ellipse (see Fig 1 in Results, for example), which is the region with increased tissue stiffness. The background ROI was defined outside the bright halo around the ablated region. The upper limit of the strain values on the EDE images was set to a maximum of 0.025 or 2.5%, which was the approximate upper limit of the strain value introduced by the small needle perturbation. For B mode images, the ROI of the ablated region was defined within the bright gas bubble region, and the background ROI was selected from a region adjacent to the bubbles.
CNR of the ablation region
CNR, the contrast-to-noise ratio takes into consideration the noise level of the ablation region and background and is used to describe the detectability of the ablated region with the EDE strain image (Varghese and Ophir 1998). The CNR of the ablation region was calculated using:
(3) |
where and represent the variance of the strain estimates within the ROI defined in the ablation region and background, respectively.
Measurement methods
Visualization and comparison of ablated regions on EDE strain and B mode images in this paper was not designed as a blinded study. A single observer with experience in ex-vivo and in-vivo MWA experiments delineated the ablated region area and selected the ROI for estimation of the contrast and CNR for both B mode and EDE strain images. B-mode images were analyzed before EDE strain images.
Statistical analysis
The area, contrast and CNR of the ablated region on EDE strain and B-mode images were compared pairwise for each patient studied. These were presented in the form of a scatter plot. Box and whisker plots were then used to perform a clustered comparison for the 40 patients, with the median value being the center bar within the box, the first and second quartile values denoted as the upper and lower borders of the box, and the 10th and 90th percentage values denoted by the top and bottom bar. The p value of the hypothesis that the values generated with EDE are greater than those with B mode images were calculated and represented with number of stars above the box and whisker plots.
Results
The high modulus contrast between the ablated region and the surrounding healthy tissue leads to a “saturated halo” appearance around the ablation zone on the EDE strain image, as shown in Fig. 1. Previous studies on TM phantoms and in-vivo porcine models have shown that the ablation zone on EDE matches histopathological ablation contours well in terms of target area and dimensions (Bharat et al. 2008b; Jiang et al. 2010; Rubert et al. 2010).
Figure 1, presents both the pre and post-ablation EDE strain and B-mode images for a patient with a 2 cm HCC diagnosed using pre-ablation magnetic resonance imaging. The liver was cirrhotic and the patient had not undergone any prior treatment for this tumor. HCC tumors are softer than normal liver tissue, and thus would be significantly softer than cirrhotic liver tissue (DeWall et al. 2012a). Note the clear visualization of two MWA antennae in the B-mode image obtained prior to the ablation, as two antennae were placed for this patient. The pre-ablation EDE strain image indicates the presence of a small stiffer region surrounding the ablation needle, due to the cyro-lock feature utilized to prevent needle movement following antenna placement, and an area of increased decorrelation at the location of the second antenna. MWA ablation was performed for 5 minutes at a 65 Watt power level in this patient. The post-ablation EDE image indicates the ablated region as an ellipsoidal region of increased stiffness (Bharat et al. 2005; Kiss et al. 2009) that incorporates the ablation region produced from both antennae. The needle track in the post-ablation images indicates the antenna that was perturbed to generate the EDE strain image in Figs. 1-3.
Ablation zones viewed on EDE were compared to those seen on conventional ultrasound B mode images in terms of ablation region area, contrast and CNR. The maximum dimension of the ablated region is outlined on Figs. 2 and 3, for both EDE and B-mode images, corresponding to the length of major axis of the low-strain region and the gas bubble cloud formed immediately after the ablation procedure. Note from Fig. 2, that the location of segment with the largest dimension in both images does not coincide, and this was the case with most of the ablations. Therefore, a more representative metric such as the ablation area and strain contrast was utilized in our analysis. Also observe in Fig. 3 that the gas bubble region does not coincide with the ablated region.
Figures 4-7, summarize the different features utilized to compare the performance of EDE based strain imaging versus conventional B-mode imaging for evaluating the ablation zone following completion of the procedure. Scatter plots present measurements from all 40 patients, with a horizontal line denoting the mean of the EDE and B-mode measurements respectively. For the box-and-whisker plots the dashed long horizontal bar in each data sets represents the median value, with the first and third quartiles defined by the box while the error bar represents the 10% and 90% values of the distribution of the measured feature values.
Ablation region area on EDE and B mode images
Figure 4(a), presents scatter plots comparing ablation areas estimated with EDE with areas of the hyperechoic regions on B-mode images. Each vertical pair of filled circles and triangles denotes values for EDE strain and B-mode respectively for the same patient. The average area of the ablation zone on EDE was 13.38 ± 4.99 (standard deviation) cm2. As a comparison, the average area on B mode images for the same patient data set was 7.61 ± 3.21 (standard deviation) cm2. A statistical comparison of the ablation area visualized on EDE strain with the area on B-mode imaging is illustrated in Fig. 4 (b).
Contrast of ablation region on EDE and B mode
In a similar manner, the distribution of the contrast obtained on the 40 patients is shown in Fig. 5(a). The mean value of the ablation zone contrast with EDE strain images was 0.73 ± 0.08 (standard deviation) while, the mean value of contrast on B mode images for the same patient data set was 0.22 ± 0.08 (standard deviation) as indicated by the horizontal lines in Fig. 5(a). The scatter plot for the contrast indicates a significant separation between the contrast estimated for EDE and the B-mode contrast of the ablated region. The distribution of contrast between the ablation area and background is shown in Fig. 5 (b). Strain imaging appears to provide a significant improvement in ablation region delineation based on the contrast (p < 0.001).
CNR of the ablated region on EDE and B mode images
Finally, the CNR distribution for both EDE strain and B-mode imaging is illustrated in Fig. 6(a). The average CNR of the ablation zone on EDE was 10.94 ± 2.45 dB (standard deviation), while the average CNR on B mode images was 5.52 ± 3.37 dB (standard deviation). Observe that the CNR is always positive with EDE, while the CNR obtained with B-mode imaging shows a few cases with extremely poor CNR leading to reduced detectability of the ablated region. The box-and-whisker plots for the CNR for EDE strain and B-mode imaging is shown in Fig. 6 (b).
A two-dimensional scatter plot depicting contrast versus the ablation area for each patient is shown in Fig. 7. Observe the separation between the B-mode estimates for the 40 patients from the EDE estimates, which exhibit a higher contrast and larger ablation areas.
Discussion
EDE was applied on patients undergoing MWA therapy as a potential modality to define the post-procedure zone of ablation in this study. Strain images obtained using EDE demonstrated improved ablation region delineation when compared to conventional B mode images in terms of ablation area, image contrast and CNR as shown in Figs. 4-7. In addition, an approach that vibrates the ablation needle to generate and image shear waves, termed electrode vibration elastography has also been developed (Bharat and Varghese 2010; DeWall and Varghese 2012; DeWall et al. 2012b; Ingle and Varghese 2014).
In conjunction with EDE, ultrasound could become an effective modality for complete monitoring of the ablation zone during MWA treatments. Although conventional B mode imaging is used routinely in the clinic for guidance in the ablation antenna/electrode placement and for monitoring outgassing, it does not clearly define the ablation zone at the completion of the procedure (Malone et al. 1994). Currently the most common method to monitor the ablation margin at the completion of the procedure is X-ray computed tomography (CT). Contrast CT, the current clinical standard for confirmation of the success of the procedure, provides ablation zone volume estimation and margin definition. However, CT may not be available during the procedure in many centers. This may necessitate a repeated ablation procedure and reinsertion of an antenna in the liver if the ablation zone does not adequately cover the targeted tumor and tissue margins. Ultrasound EDE is nonionizing, and thus can be performed without radiation exposure to either the patient or physician. The demographics of the patients involved in this study was 10 female and 34 male, ranging in age from 33 to 83, which is summarized in Table 1.
Table 1.
Patient features | Value |
---|---|
Age | 64.4 ± 9.3 years |
Gender (M/F) | 34/10 |
Tumor size | 2.2 ± 0.8 cm |
Cirrhosis (Y/N) | 37/7 |
Fatty Liver (Y/N) | 1/43 |
Prior Treatment (Y/N) | 10/34 |
It is important when treating with RFA to limit variations in thermal dose within the ablation volume and to avoid delivery of an incomplete dose to tumors, including those that are adjacent to large vessels (Lencioni and Crocetti 2012). This limits the application of RFA to smaller tumors and ones away from large vessels (unless other precautions are taken). Large tumors and ones near large vessels show a decrease of up to 50% in terms of complete tumor necrosis (Lencioni and Crocetti 2012). An adequate ablation margin around the tumor region is a key factor for the success of percutaneous ablation treatments (Lencioni and Crocetti 2007; Lencioni and Crocetti 2012; Maluccio and Covey 2012). Various studies suggest that the margin should extend between 0.5 – 1.0 cm into the tumor free region (Lencioni and Crocetti 2007; Lencioni and Crocetti 2012; Maluccio and Covey 2012). Thus, an effective thermal ablation margin monitoring method is crucial to guarantee a successful clinical outcome. Immediately following ablation therapy, a hyperechoic area is observed on ultrasound B-mode images due to out-gassing of water vapor, which resolves within about 10 minutes after the procedure. The ablated region with MWA is slightly hyperechoic centrally and around the periphery and hypoechoic elsewhere (Wells et al. 2015b; Ziemlewicz et al. 2016). Contrast-enhanced ultrasound imaging has also been useful in delineating HCC tumors pre-ablation (Minami and Kudo 2011) and the coagulated region post-ablation (Clevert et al. 2012).
Even in cases where ablation area estimations on B mode images were relatively close to those obtained on EDE strain, estimations of ablated areas on B mode images was always smaller due to a shadowing effect, as seen in Fig. 3. In Fig. 3 (b) the gas bubbles tended to accumulate towards the top of the ablation zone and thus the lower boundary of the ablation zone was blurred due to the shadowing effect caused by increased attenuation from the gas bubbles. Thus it was difficult to visualize the thermal dose distribution on the bottom half of the ablated region on B mode images, and this increases the uncertainty for physicians to judge if an adequate ablation margin has been applied uniformly around the ablation zone. On the other hand, as shown in Fig 3 (a), the ablation zone could be clearly identified on EDE strain. Thus the thermal dose distribution along any direction can be easily observed.
Based on the estimated ablation areas, EDE strain images were not significantly affected by tumor depth as illustrated in Table 2. EDE provides delineation of the ablated region for treated HCC regions both at shallow depths and for deeper ablated tumor regions. This result is unlike that reported for elastographic imaging using acoustic radiation force, which is generally limited by ultrasonic attenuation to depths lower than 8 cm (Zhao et al. 2011; Deng et al. 2015).
Table 2.
HCC Depth | HCC Number |
EDE Success | EDE Success Rate |
---|---|---|---|
< 5 cm | 9 | 8/9 | 88.9% |
> 5 cm < 8 cm | 22 | 20/22 | 90.9% |
> 8 cm < 10 cm | 5 | 5/5 | 100% |
> 10 cm < 15 cm | 8 | 7/8 | 87.5% |
Total | 44 | 40/44 | 90.9% |
The major limitation of this study was the lack of real-time EDE imaging feedback to the physicians. Image processing was performed offline on an Intel Core 2 desktop computer. The average processing time for each EDE strain image was approximately one minute. In order to obtain real time feedback, a higher performance system or more efficient programming techniques would be necessary. This lack of real-time feedback also potentially affected the success rate of EDE strain imaging. We performed EDE on 44 patients and obtained successful strain imaging results in terms of distinguishable ablation zones on 40 of the 44 patients. The success rate was 90.9%, which would have been considerably improved by the immediate feedback that real-time imaging would have provided to the physician (Hall et al. 2003). Real-time feedback would allow physicians to more easily standardize the applied deformation using the ablation antenna. Several vendors currently do provide such feedback on their commercial elastography software, and this aspect can be easily addressed for this clinical application (Hall et al. 2003).
A second limitation of the study is the lack of ultrasound or EDE based volume information on the ablated region. We have previously demonstrated that three-dimensional volume reconstruction of ablated regions using EDE can be obtained (Bharat et al. 2008a), however a viable method of obtaining three-dimensional imaging information clinically in patients is essential. This can be done either with two-dimensional ultrasound arrays or more efficient scanning approaches (Ingle and Varghese 2014).
Side effects of EDE
The magnitude of the perturbation applied to the ablation antenna is within 1-2 mm. During the deformation of surrounding tissue and the ablated region, no relative slip between the surrounding tissue and ablation antenna was observed with EDE prior to or after the MWA procedure. There were no obvious side effects with EDE since the positioning of the ablation antenna was not affected after data acquisition. Because of the small range of displacements introduced by the antenna, the ablation procedure is not adversely affected (Varghese et al. 2002; Kolokythas et al. 2008; Varghese 2009).
Conclusions
In this paper we demonstrate that EDE is feasible during MWA procedures of HCC tumors regardless of tumor depth. EDE strain images provide improved ablation region delineation compared to conventional B mode imaging. Further work needs to be performed to assess the accuracy of the ablation margin delineated by EDE and whether the entire tumor with sufficient surrounding normal tissue has been treated. Comparison of EDE results to a clinical gold standard such as contrast enhanced CT is therefore essential.
Acknowledgements
This study was funded by NIH grant 2R01 CA112192. We are grateful to Siemens Medical Solutions USA, Inc., for providing the S2000 Axius Direct Ultrasound Research Interface (URI) and Software licenses.
Funded by NIH grant 2R01 CA112192.
Footnotes
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