In 2007, Sonazoid, a new microbubble contrast media agent, was approved for use in Japan for the diagnosis of liver tumors, however, which has not been well applied in the western and other countries so far. [6–8, 16, 17, 23–25] In the biliary and pancreas diseases, Sonazoid is usually applied to detect early phase vascular flow and perfusion pooling in the normal organs contrary to various malignant diseases as well as liver diseases. In this study, we emphasize the usefulness of Sonazoid-US for the intraoperative diagnosis to decide the final decision of treatment strategy limited in the disease in case it was difficult to distinguish differential diagnosis in this study. Therefore, this examination has not been routinely applied for all surgeries for biliopancreatic diseases and the selected subject was not many for 10 years in this series. The previous reports showed that diagnostic accuracy of vascularity or disease diagnosis by Sonazoid-US was not inferior to those by ultrasonography using sulphur hexafluoride microbubbles (SonoVue) which is a similar agent with shell and has been well applied other worldwide countries. [8, 26–28] Park et al. reported that Sonazoid produced higher values of peak intensity of enhancement, wash-in rate, and area under curve of enhancement of pancreas in comparison with those of SonoVue in animal model. [29] The introduction of this modality markedly improved the diagnostic accuracy of liver tumors to levels similar to those of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid-magnetic resonance imaging (MRI). [13, 16, 24] The use of Sonazoid IOUS has allowed the detection of occult lesions or tumor spreading undetected by conventional US. [17, 25] Particularly, Kupffer-phase imaging is a powerful diagnostic tool to identify even small-sized abnormal nodules. [23, 24] The usefulness of IOUS has been well realized and is considered to be a reliable imaging technique often used to confirm the diagnosis of intrahepatic tumor lesions. [5, 9] In the present study, we expected that contrast IOUS using Sonazoid would enhance the detection of biliopancreatic lesions based on defining tumor vascularity and aid in the determination of sufficient surgical margin. The advantages of contrast IOUS using Sonazoid were recently reported in patients with liver tumors in our studies. [14, 15] However, the significance of IOUS using Sonazoid has not been fully investigated in biliary and pancreatic neoplasms [16–20] to our knowledge, and, therefore, its clinical usefulness has not been fully recognized. In the present preliminary study, we assessed the usefulness of Sonazoid IOUS in the detection of various biliopancreatic neoplasms and the compared benign diseases. Sonazoid injection was extremely safe without severe side effects. [30]
Using the same Sonazoid IOUS protocol described in previous studies, [14, 15, 23] we examined the early arterial phase first followed by vascularity in the portal phase during laparotomy in the present study. Sonazoid IOUS allows searching of the entire liver or pancreas over a relatively long period by screening for parenchymal perfusion. In the present series, all diseases could be detected by either plain IOUS or Sonazoid IOUS. Among the limited number of 24 patients in this study, we attempted to determine non-GC lesions in 13 patients as a control Interestingly, GAM or adenoma as a control lesion showed enhancement of over 50%, and therefore, a significant difference in enhancement compared with that in GC was not observed. These benign lesions might have similar hypervascularity and malignancy. However, VA did not show vascularity regardless of it having similar biliary malignancy. Although tumor location can be well detected, ruling out a diagnosis between benign and malignant biliopancreatic disease might be difficult based on our results, even though Sonazoid IOUS was used. Other reports of contrast US findings in biliopancreatic diseases were reviewed between 2005 and 2020, and only a few investigated Sonazoid US for gallbladder carcinomas. [31, 32] Sugimoto et al. showed only that contrast-enhanced endoscopic US enabled real-time observation of the hemodynamics of gallbladder tumors, which was applied for the diagnosis of malignancy. [31] Imazu et al. showed the usefulness of contrast-enhanced harmonic endoscopic US with Sonazoid in preoperative T-staging for pancreaticobiliary malignancies. [32] However, neither report showed an enhancement effect for conditions resembling cholecystitis or adenoma of the gallbladder. Our results showed that these conditions were also enhanced by Sonazoid IOUS due to tumor vascularization although the positive rate tended to be lower but not significantly different than that for gallbladder cancer. Sonazoid seems difficult to use for a differential diagnosis even with sensitive IOUS. However, tumor location or extension including infiltration could be well detected both by hypervascularity in the early phase and wash-out or by hypoechoic lesions contrasting with the surrounding gallbladder wall and liver parenchyma. Thus, this modality appears to be a more useful imaging procedure in comparison to conventional IOUS. A few investigators reported vascularity in bile duct adenoma or hamartoma. [33–37] In our series, a cholesterol polyp was not enhanced due to less vascularity, as in the report by Yu et al., [36] and, interestingly, debris formation resembling or adjacent to the main gallbladder cancer showed strong enhancement. Hyperechoic artifacts were sometimes seen in sludge or debris due to entrapment of cholesterol crystals, which may influence US detection. However, it is difficult to clearly explain the mechanism for this. The rare intrahepatic bile duct adenoma did not show enhancement by Sonazoid US contrary to the report by Wei et al. and findings in other adenomatous regions. [34] We speculated that the adenomatous origin was different from that of other adenoma.
Several reports also showed the effectiveness of Sonazoid US with respect to the intra-pancreas region. [31, 32, 37] VA is one of the bile duct carcinomas and usually shows delayed hypervascularity on contrast-enhanced computed tomography (CT). However, no vascularity was observed with Sonazoid IOUS in our patient. In contrast, serous multi-cystic adenoma with hypervascularity, which was suspected to be a pancreatic cancer, showed strong enhancement with Sonazoid use. Basically, the pancreatic parenchyma showed lower enhancement than that of the liver parenchyma. However, as a negative contrast imaging technique, this procedure may be able to detect multiple metastases or invasive extent, which would be more suited to the field of pancreatic surgery. Thus, further studies in a larger series of biliopancreatic disease patients will be necessary to clarify the echogenicity of disease vascularity.
Occult metastatic lesions, which are often newly detected by IOUS in around 20% of patients, require additional resection. [38, 39] In the present study, occult metastatic lesions were not detected using Sonazoid IOUS, which was different than when Sonazoid IOUS is used to detect occult metastatic lesions of intrahepatic malignancies. Metastatic lesions of GC or VA were detected in two of our patients, but these lesions were also detected by conventional IOUS. However, in comparison with preoperative CT or MRI, conventional and Sonazoid IOUS are useful to detect small accessory lesions during surgery. [14, 15] This information is useful to avoid performing intraoperative surgical treatment that is too invasive. Although we did not attempt it, this imaging modality can be routinely applied before surgery in patients with gallbladder or extrahepatic biliary diseases in accompaniment with enhanced MRI. Based on the results of this preliminary study, the usefulness of Sonazoid IOUS was estimated, and therefore, further study with a larger number of patients will be necessary as the next step.