Ann Surg Oncol DOI 10.1245/s10434-014-3576-y


Usefulness of Contrast-Enhanced Intraoperative Ultrasound in Identifying Disappearing Liver Metastases from Colorectal Carcinoma After Chemotherapy Junichi Arita, MD, PhD, Yoshihiro Ono, MD, PhD, Michiro Takahashi, MD, Yosuke Inoue, MD, PhD, Yu Takahashi, MD, PhD, and Akio Saiura, MD, PhD Gastroenterological Surgery Department, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan

ABSTRACT Background. Preoperative chemotherapy sometimes makes colorectal liver metastases disappear or diminish. Contrast-enhanced intraoperative ultrasound (CE-IOUS) using perflubutane may identify such metastases. Methods. Among 131 consecutive patients who underwent hepatic resection, 86 had received preoperative chemotherapy. Of these patients, 72 were examined using contrastenhanced computed tomography (CE-CT), gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI), contrast-enhanced ultrasound (CEUS), intraoperative ultrasound (IOUS), and CE-IOUS; these patients were the subject of the present study. Effects of IOUS and CE-IOUS to search for disappearing liver metastases (DLM) and tumors with a diameter of 1 cm or less based on the preoperative imaging were assessed. Results. A total of 32 DLMs were noted in 11 patients. Four DLMs were identified using IOUS, and 16 DLMs (including the four DLMs identified using IOUS) were identified using CE-IOUS. Of the 16 DLMs that were missed using both IOUS and CE-IOUS, nine were resected using anatomical resection and seven were not resected. One of the nine resected DLMs was histologically proven to be adenocarcinoma. Three of the seven unresected DLMs showed tumor regrowth during a postoperative follow-up examination. CE-IOUS identified 79 % of the 19 DLMs that were ultimately confirmed as liver metastases, whereas IOUS identified 21 % of them (p \ 0.004).

Ó Society of Surgical Oncology 2014 First Received: 20 October 2013 J. Arita, MD, PhD e-mail: [email protected]

Among the 202 tumors that were identified using preoperative imaging, 54 were 1 cm or less in diameter. The sensitivity of CE-IOUS for these tumors were superior to CE-CT (p \ 0.04) and IOUS (p \ 0.04), respectively. Conclusions. CE-IOUS might be necessary after preoperative chemotherapy for colorectal liver metastasis.

Chemotherapy for liver metastasis from colorectal carcinoma has been rapidly advanced with the development of molecular target agents. An increasing number of patients who have initially unresectable metastases benefit from chemotherapy through conversion to hepatic resection by tumor reduction.1 Additionally, some reports have advocated a survival benefit of neoadjuvant chemotherapy followed by hepatic resection, even in patients with initially resectable metastases.2 The shrinkage of liver metastases by chemotherapy sometimes makes such tumors impossible to identify in imaging studies; these lesions are called ‘disappearing liver metastasis’ (DLM) or ‘missing liver metastasis’.3,4 In patients undergoing liver surgery, the accurate resection of a DLM is difficult if the metastasis cannot be identified during the operation. Intraoperative ultrasound (IOUS) has been used as a key tool for this purpose to date, but only 10–30 % of DLMs are reportedly identified using IOUS.5–7 Thus, a new technique capable of detecting a larger proportion of DLMs than the conventional method is needed. Contrast-enhanced intraoperative ultrasound (CE-IOUS) is a novel technique that is capable of detecting a larger proportion of liver metastases than conventional imaging modalities, including IOUS.8–10 Previously reported contrast agents for ultrasound included sulfurhexafluoride and perflubutane. Both of these agents are capable of visualizing the vascularity of a hepatic tumor; however, perflubutane is

J. Arita et al.

unique in that it accumulates in Kupffer cells, thereby enabling Kupffer imaging.11–13 The use of CE-IOUS, in addition to conventional IOUS, for the detection of DLMs has not been previously reported. In this study, the usefulness of CE-IOUS using perflubutane to detect DLM was assessed in patients who had been preoperatively examined using all of the following imaging modalities: gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) enhanced magnetic resonance imaging (EOB-MRI) [a novel modality enabling liver-specific images 14,15], contrast-enhanced computed tomography (CE-CT) (the gold-standard for the preoperative diagnosis of colorectal liver metastasis), and contrast-enhanced ultrasound (CEUS).

Hepatic resection with curative intent, 131 Pts Preoperative chemotherapy (–), 45 Pts Preoperative chemotherapy, 86 Pts CE-IOUS (–), 3 Pts CE-CT and EOB-MRI (–), 3 Pts Imaging protocol completed, 80 Pts 12 or more tumors, 8 Pts Subjects, 72 Pts

METHODS Minimal tumor size just before operation

Patients This retrospective study was based on data extracted from a prospective study (UMIN000005537; jp/ctr/index.htm) and was approved by the Institutional Review Board of the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. Written informed consent was obtained from all patients. Among 131 consecutive patients undergoing curative hepatic resection for liver metastasis from colorectal carcinoma between January 2011 and July 2012, a total of 86 patients received preoperative chemotherapy, which had finished 12 months or less before hepatic resection. Among these, 80 patients were examined using CE-CT, EOB-MRI, preoperative CEUS, IOUS, and CE-IOUS. Of the remaining six patients, two were unable to undergo CE-CT and EOB-MRI because of a history of asthma, and one patient was unable to undergo these examinations because of renal dysfunction. Furthermore, three patients did not undergo CE-IOUS because they had received a laparoscopic hepatectomy. Among the 80 patients who underwent all the above-mentioned examinations, eight patients in whom more than 12 liver metastases were ultimately diagnosed in each case were excluded because the accurate identification of the numerous tumors was difficult. Consequently, the imaging results for 72 patients were analyzed in the present study (Fig. 1). Neoadjuvant chemotherapy was performed within 2 months before hepatic resection in 28 patients, chemotherapy was induced for liver metastases, ± lung metastasis, ± lymph node metastasis and a therapeutic conversion to hepatic resection was achieved in 16 patients, adjuvant chemotherapy after resection of colorectal carcinoma or liver metastasis was started but liver metastasis emerged during chemotherapy duration in ten patients, and adjuvant chemotherapy was completed followed by development of liver metastasis in 18 patients.

> 1 cm 30 Pts

0.5–1 cm 17 Pts

0.5 0.5cm cm 14 Pts

Disappeared 11 Pts

FIG. 1 Flowchart indicating patient selection according to the preoperative, intraoperative, and postoperative procedures. Pts patients, CE-IOUS contrast-enhanced intraoperative ultrasound, CECT contrast-enhanced computed tomography, EOB-MRI gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging

Preoperative Imaging Studies The CT systems used in this study consisted of an 80detector row device (Aquilion Prime; Toshiba Medical, Tokyo, Japan) and a 16-detector row device (Light Speed 16; GE Medical Systems, Milwaukee, WI, USA). The collimation, pitch factor, rotation time, and tube voltage were 80 9 0.5 mm and 16 9 2.5 mm, 0.813 and 1.375, both 0.5 s, and both 120 kV, respectively. Scanned images were obtained in 5-mm sections. CT scans were performed at 35 and 90 s after the start of injecting 300 mgI/mL of non-ionic contrast material at a dose of 2 mL/kg body weight; images obtained at both the timings were referred for diagnosis of liver metastasis. The EOB-MRI examinations were performed using 1.5T system (Excelart Vantage 1.5 T, Toshiba Medical, Tokyo, Japan; or Signa Excite HD 1.5 T, GE Medical Systems, Milwaukee, WI, USA). The imaging protocol included a fat-suppressed, three-dimensional (3D) fast field echo (Excelart Vantage) or a 3D liver acquisition with volume acceleration (Signa Excite HD), and a T1-weighted sequence before and after the injection of contrast material. For both systems, the acquisition time was 18–23 s and 18–

CE-IOUS for Disappearing Liver Metastasis

22 s, the repetition time was 5.5 and 4.6 ms, the echo time was 2.5 and 2.1 ms, the flip angle was 12° each, the field of view was 30–38 cm each, the slice thickness was 6 mm each, and the matrix size was 336 9 192 and 256 9 256, respectively. During the dynamic study, each patient was given 25 lmol/kg (0.1 mL/kg) of Gd-EOB-DTPA (Primovist; Bayer Schering Pharma AG, Berlin, Germany) in 7.5 s, followed by a 20 mL saline flush at a rate of 2 mL/ s. The arterial, portal, and delayed phases were obtained during each single breath-hold with a scan delay of 25, 60, and 120 s, respectively. After the dynamic study, hepatobiliary phase imaging was obtained 15–20 min after the injection. The gradual hepatocyte uptake of this contrast agent makes the normal liver parenchyma hyperintense during the hepatobiliary phase. In contrast, colorectal liver metastases appear as hypointense areas and thus are well delineated with a clear contrast from the surrounding liver parenchyma. A T2-weighted fast spin echo sequence was also obtained using the following settings: repetition time, 2650 ms; echo time, 90 ms; flip angle, 90°; field of view, 35–38 cm; and slice thickness, 5 mm. One or more expert radiologists read each of the CE-CT or EOB-MRI images; the radiologists were not blinded to the results of prior imaging studies. CEUS was typically performed on the day before the operation. After a conventional transcutaneous ultrasound, a bolus of 4 lL of perflubutane suspension (Sonazoid; GE Healthcare, Oslo, Norway) was injected through a peripheral vein. At 10–15 min after the contrast injection, the whole liver was systematically screened using a harmonic mode dedicated for detection of perflubutane. The microbubbles of perflubutane had accumulated within the Kupffer cells of the liver, and the surrounding liver became hyperechoic, demonstrating liver metastasis as a welldelineated hypoechoic lesion. CEUS and subsequent tumor staging were performed by an attending physician who had been performing abdominal ultrasound examinations for 5 years or more. CE-CT, EOB-MRI, and CEUS were performed within 1 month prior to the operation; if not, the imaging examination was performed again immediately before operation. Intraoperative Ultrasound and Contrast-Enhanced Intraoperative Ultrasound Following a laparotomy and liver mobilization, conventional IOUS was performed to confirm the preoperative tumor staging and to search for new occult liver nodules. After IOUS, a bolus of perflubutane suspension was injected through a peripheral vein at a microbubble dose of 4 lL. A systematic ultrasonic liver screening was then performed using the harmonic mode at 10–15 min after contrast injection, with the focus point set at the bottom of

the liver (CE-IOUS). Any hypoechoic liver nodule that was visible during CE-IOUS was considered to be a liver metastasis, except for the nodules that were diagnosed as cyst or hemangioma using the preoperative CE-CT and EOB-MRI. All the IOUS and CE-IOUS procedures were performed by an attending surgeon who had over 7 years of experience performing IOUS. The ultrasound system Aplio MX (Toshiba, Tokyo, Japan) was used for all the IOUS and CE-IOUS procedures. PLT-705BTH (Toshiba, Tokyo, Japan), a linear probe dedicated for IOUS with a 6.6 MHz transmit and receive center frequency, was used for all the IOUS and CE-IOUS examinations. CEUS and CE-IOUS were performed using the Pulse Subtraction Coded Harmonic Imaging mode (Toshiba, Tokyo, Japan), a harmonic mode dedicated to the detection of microbubbles of perflubutane. The frame rate was set at 60 Hz in the fundamental mode and 23 Hz in the harmonic mode. For all the CE-IOUS procedures, the mechanical index and dynamic range were set at 0.18 and 40 dB, respectively. Treatment of Liver Nodules All the hepatic nodules that were identified by any of the preoperative imaging examinations and that were ultimately diagnosed as liver metastases were included in the initial analysis. Among these liver metastases, those that had decreased to 1 cm or less or that had disappeared on preoperative images after chemotherapy were analyzed. DLM was defined as a liver metastasis that had shrunk because of preoperative chemotherapy and was missed in all the images performed immediately before hepatic resection. The diameter of each nodule was measured using the resected specimen in principle. If a nodule was not identified in the specimen, the diameter was decided referring the preoperative images. Liver metastases that had never been identified using any preoperative images but that were initially found during IOUS, CE-IOUS, or the histological examination of the resected specimen were excluded. Nodules were resected, in principle, when they were tentatively diagnosed as a liver metastasis based on any of the preoperative or intraoperative imaging studies. If the resection of such a nodule was impossible for safety reasons, a core needle biopsy of the nodule was conducted under IOUS guidance. In principle, DLMs were resected based on the results of previous reports that the majority of unresected DLMs ultimately exhibit regrowth during a postoperative follow-up period.3,5–7 If the DLM could not be identified using either IOUS or CE-IOUS, an attempt was made to eradicate the nodule using an anatomical resection of perfusion volume of tumor-harboring portal triad referring the images obtained before chemotherapy,

J. Arita et al. TABLE 1 Characteristics of patients with and without DLM

Identified before chemotherapy (n = 234)


Age [years (range)]

Images just before operation

Identified (n = 202)

0.6–1 cm (n = 40)

DLM (n = 32)

RESULTS A total of 234 liver metastases were identified in all 72 patients based on imaging studies performed before chemotherapy. After chemotherapy, 32 DLMs (14 %) were

64 (30–84)






0.40 0.006a,*
















Agent included in regimen Oxaliplatin












Cetuximab/ panitumumab



0.003* 0.032b, *

Modified Kleiner score 0














5 0 Hepatectomy procedure




Limited resection











Repeated 1/10 hepatectomy (yes/no)

Statistics All the statistical analyses were performed using commercially available software (PASW Statistics 17.0.2; SPSS, Chicago, IL, USA) for Microsoft Windows. All continuous variables were summarized as the median and range. The Mann–Whitney U test was applied to compare continuous variables between two groups. The Fisher’s exact test was applied to compare proportions between two groups. The McNemar test was applied to compare the diagnostic abilities between two imaging modalities. Statistical significance was assessed using a two-tailed test at p \ 0.05.

61 (42–81) 7/4

FIG. 2 Flowchart indicating classification of tumors according to the preoperative imaging examinations. DLM disappearing liver metastases

known as ‘blind hepatectomy’, so long as the safety of the patients could be secured. Unresected nodules were followed-up postoperatively using CE-CT or EOB-MRI examinations performed every 3–6 months. Radiofrequency ablation was never done in this study. Chemotherapy-induced liver damage was quantified using the total sum of graded scores for steatosis (0–3), sinus dilatation (0–2), lobular inflammation (0–3), and ballooning (0–2), which represents a modification of the ‘Kleiner score’,16 and which indicates the extent of non-alcoholic steatohepatitis, taking sinusoidal obstruction into consideration.

p value

Primary site (rectum/ colon) Number of liver metastasis

Not identified (n = 32)

0.1–0.5 cm (n = 14)

Without DLM (n = 61)

Sex (men/women)

Tumor size

> 1 cm (n = 148)

With DLM (n = 11)

16 18/43


DLM disappearing liver metastases * Indicates statistically significant a Single versus multiple b

0 versus 1 or more


Segmentectomy or less versus sectionectomy or more

recognized in 11 patients (15 %), and 54 nodules with a diameter of 1 cm or less were recognized among the other 202 nodules (Fig. 2). Characteristics of the patients with and those without DLMs are summarized in Table 1. Compared with patients without DLMs, a larger proportion of patients with DLMs had multiple liver metastases (p = 0.006), had received chemotherapy, including epidermal growth factor receptor (EGFR) inhibitor agents, namely cetuximab and panitumumab (p = 0.003), and had background liver damage based on a histological examination (p = 0.032).

CE-IOUS for Disappearing Liver Metastasis

FIG. 3 Flowchart of disappearing liver metastases indicating treatment and diagnosis on intraoperative and postoperative procedures. DLM disappearing liver metastases, IOUS intraoperative ultrasound, CE-IOUS contrast-enhanced IOUS

TABLE 2 The sensitivities of the imaging modalities for small liver metastases that were identified preoperatively Tumor size (cm)

CE-CT (%)


CEUS (%)

IOUS (%)


0.1–0.5 [n = 14]






0.6–1.0 [n = 40] Total [n = 54]

93 89

93 93

64 76

86 89

100 100

CE-CT contrast-enhanced computed tomography, EOB-MRI gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging, CEUS contrast-enhanced ultrasound, IOUS intraoperative ultrasound, CE-IOUS contrast-enhanced IOUS

A flowchart describing the DLMs is shown in Fig. 3. Four nodules were initially identified using IOUS, 12 nodules were initially identified using CE-IOUS, and the other 16 nodules could not be identified intraoperatively. All four nodules identified using IOUS were also identified as hypoechoic lesions using CE-IOUS. All four nodules that were identified using IOUS and 11 of the 12 nodules that were identified using CE-IOUS were histologically confirmed as metastases. The medians (ranges) of the diameters of the histologically confirmed DLMs that were initially identified using either IOUS (n = 4) or CE-IOUS (n = 11) were 0.3 (0.2–0.6) cm and 0.45 (0.2–0.7) cm, respectively (p = 0.412). One DLM was initially identified using CEIOUS as a 0.3-cm hypoechoic lesion but was missed in all 3mm-thick slices of the resected specimen. Sixteen DLMs were missed intraoperatively, but nine of them were resected

using ‘blind hepatectomy’, as mentioned above. Only one of these nine nodules was histologically confirmed as a metastasis, although tumor was histologically searched in 3mm-thick slices. Of the seven nodules that were missed intraoperatively and that were followed-up using postoperative imaging studies (unresected because surgical safety was not secured), three nodules showed regrowth at the same site at 6, 9, and 9 months after surgery, respectively. No tumorous lesions were seen at the sites of the other four nodules for 12, 12, 14, and 18 months after surgery, respectively. For the true-positive metastases, which were defined as the 19 DLMs that were either histologically confirmed as metastasis or that showed regrowth during the follow-up period, the sensitivities of IOUS and CE-IOUS were 21 and 79 %, respectively, and the accuracies were 53 and 84 %, respectively (p \ 0.004).

J. Arita et al.

Among the 202 liver metastases that were identified using at least one of the preoperative images, 14 nodules in 9 patients were 0.1–0.5 cm (smaller group) and 40 nodules in 24 patients were 0.6–1 cm (lager group) [Fig. 2]. Among the 14 nodules in the smaller group, two nodules were missed using IOUS, whereas all 14 nodules were identified using CE-IOUS. Among the 40 nodules in the larger group, four nodules were missed using IOUS (0.7–1 cm) but all the nodules were identified using CE-IOUS. The sensitivities of CE-CT, EOB-MRI, CEUS, IOUS, and CE-IOUS for the respective groups are presented in Table 2. For both the smaller and the larger groups, no significant differences between any pair of imaging modalities were seen; however, for the total tumors with a diameter of 1 cm or less, significant differences in sensitivity were observed between CECT and CE-IOUS (p \ 0.04) and between IOUS and CEIOUS (p \ 0.04). DISCUSSION This study showed that CE-IOUS using perflubutane is useful for identifying the liver metastases that were missed during preoperative imaging after preoperative chemotherapy, i.e. DLMs. If a DLM is missed using conventional IOUS, which has been considered to be the ultimate imaging technique, precise eradication of the tumor can be difficult. However, nearly half of the DLMs that were missed using IOUS were identified using CE-IOUS, potentially enabling a resection capable of preventing intrahepatic recurrence. Whether the routine use of CE-IOUS can improve recurrencefree survival remains to be clarified. Some studies have reported that half or even more of all DLMs are ultimately shown to be viable based on either histological examination or postoperative follow-up.3,5–7 DLMs, therefore, may need to be resected, and the inability to visualize DLMs intraoperatively might necessitate a ‘blind hepatectomy’, which can lead to a significant loss of liver parenchyma and might threaten surgical safety. In the present study, CE-IOUS was more sensitive at visualizing preoperatively identified liver metastases that were 1 cm or less in size than CE-CT, CEUS, or IOUS. Because the attending surgeons performed IOUS and CE-IOUS sequentially based on information obtained from preoperative images, IOUS could theoretically be expected to be more sensitive than the preoperative imaging techniques, and CE-IOUS could be expected to be more sensitive than IOUS. In fact, the sensitivity of CE-IOUS for tumors 1 cm or less reached 100 %, which was notably higher than the sensitivities of CE-CT, EOB-MRI, and CEUS. This result is compatible with the high sensitivity of CE-IOUS for detecting DLMs. Chemotherapy causes hepatic parenchymal damage, such as steatohepatitis17 and sinusoidal obstruction syndrome,18 which complicates the detection of

tumors.19,20 The above-mentioned results suggest that CEIOUS is more capable of identifying tiny liver metastases than conventional imaging protocols against a chemotherapyinduced background of parenchymal injury, a point that to the best of our knowledge has never before been addressed. One advantage of this study was the strict application of the preoperative imaging protocol. The definition of DLM is largely influenced by the preoperative imaging modalities that are used, but a uniform combination of preoperative imaging modalities has seldom been adopted in the previous reports addressing DLM.3,5–7,21–23 EOB-MRI is a novel technique that enables not only a dynamic imaging study, but also liver-specific imaging. Considering that dynamic MRI itself is reportedly superior to dynamic CT for demonstrating and characterizing liver tumors,24,25 EOB-MRI could potentially be a highly sensitive method for detecting colorectal liver metastases.15,26,27 CEUS using perflubutane provides additional value to conventional ultrasound for diagnosing colorectal liver metastasis.28,29 Moreover, all the preoperative images were obtained within 1 month prior to operation. These above-mentioned advantages likely contribute to the consistency and reproducibility of the present study. There was one false-positive nodule among all DLMs, which was identified during CE-IOUS but was missed in a histological examination. One possible reason for this misdiagnosis might be because the nodule was hidden within a 3-mm-thickness slice, which seems rare. Another reason might be because a non-tumorous lesion without Kupffer cells, such as a regenerative nodule and a fatty spared area near the DLM, was demonstrated during CEIOUS. The incidence of DLM in the present study was 15 % (11 patients of 72), which was comparable to previously reported values.3,6,7,21 Compared with patients who did not have DLM, a larger proportion of patients who had one or more DLMs had multiple liver metastases, had received preoperative chemotherapy that included an EGFR inhibitor, and exhibited chemotherapy-induced liver injury. These results seem reasonable since the summed possibility that any one of all the tumors might disappear would theoretically be higher for patients with a larger number of liver metastases as the identification of tiny tumors in injured liver parenchyma is likely to be difficult, and EGFR inhibitors reportedly induce rapid tumor shrinkage.30 One drawback of the present study was its non-blinded setting. Blind image-reading is essential for assessing the independent diagnostic ability of an imaging modality. Nevertheless, since the main object of the present study was to assess the additional value of CE-IOUS in a typical clinical setting, with surgeons performing IOUS and CEIOUS based on the results of a specific preoperative

CE-IOUS for Disappearing Liver Metastasis

imaging protocol, blind reading was not performed in the present study. CONCLUSION CE-IOUS might be necessary for patients with colorectal liver metastases who have undergone preoperative chemotherapy, even if extensive preoperative imaging studies have been completed. ACKNOWLEDGMENT This work was supported in part by a grant-in-aid from Kurokawa Cancer Research Foundation; a grant-inaid from Mitsui Life Social Welfare Foundation; and a grant-in-aid from Takeda Science Foundation. DISCLOSURES Junichi Arita, Yoshihiro Ono, Michiro Takahashi, Yosuke Inoue, Yu Takahashi, and Akio Saiura have no commercial interest in the subject of study and the source of any financial or material support.

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Usefulness of contrast-enhanced intraoperative ultrasound in identifying disappearing liver metastases from colorectal carcinoma after chemotherapy.

Preoperative chemotherapy sometimes makes colorectal liver metastases disappear or diminish. Contrast-enhanced intraoperative ultrasound (CE-IOUS) usi...
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