Improved detection of liver metastasis using Kupffer-phase imaging in contrast-enhanced harmonic EUS in patients with pancreatic cancer (with video)

      Background and Aims

      Kupffer-phase imaging visualized by perfluorobutane (Sonazoid) distribution into normal liver tissues upon phagocytosis by Kupffer cells potentially aids in improving detection of liver metastasis compared with fundamental B-mode EUS (FB-EUS). However, the diagnostic performance of Kupffer-phase imaging in contrast-enhanced harmonic EUS (CH-EUS) remains unclear. Hence, this study aimed to evaluate the usefulness of CH-EUS-based Kupffer-phase imaging for diagnosing liver metastasis from pancreatic cancer.


      We retrospectively analyzed consecutive patients with pancreatic cancer who underwent contrast-enhanced CT (CE-CT) and FB-EUS, followed by CH-EUS, from 2011 to 2017. The diagnostic ability of CH-EUS against that of CE-CT and FB-EUS for metastasis in the left liver lobe was compared. Subsequently, the influences of CH-EUS on the determination of clinical stage and patient management for pancreatic cancer were assessed.


      We enrolled 426 patients with pancreatic cancer. Metastasis in the left liver lobe was present in 27.2% of patients. The diagnostic accuracy of CE-CT, FB-EUS, and CH-EUS was 90.6%, 93.4%, and 98.4%, respectively. The sensitivity and diagnostic accuracy of CH-EUS for metastasis in the left liver lobe were significantly higher than those of FB-EUS or CE-CT. The sensitivity of CH-EUS for detecting small liver metastasis (<10 mm) was considerably higher than that of CE-CT or FB-EUS (P < .001). In 2.1% of patients, only CH-EUS could detect a single distant metastasis of the left liver lobe, thereby upgrading the tumor staging and altering the clinical management.


      CH-EUS-based Kupffer-phase imaging increased the detectability of metastasis in the left liver lobe. This technique could be a reliable pretreatment imaging modality for clinical decision-making in patients with pancreatic cancer.


      CE-CT (contrast-enhanced computed tomography), CH-EUS (contrast-enhanced harmonic endoscopic ultrasonography), EOB-MRI (Gd-ethoxybenzyl-diethylenetriaminepentaacetic acid-enhanced magnetic resonance imaging), FB-EUS (fundamental B-mode endoscopic ultrasonography), IQR (interquartile range)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Gastrointestinal Endoscopy
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Wong M.C.S.
        • Jiang J.Y.
        • Liang M.
        • et al.
        Global temporal patterns of pancreatic cancer and association with socioeconomic development.
        Sci Rep. 2017; 7: 3165
        • Egawa S.
        • Toma H.
        • Ohigashi H.
        • et al.
        Japan Pancreatic Cancer Registry; 30th year anniversary: Japan Pancreas Society.
        Pancreas. 2012; 41: 985-992
        • Wernecke K.
        • Rummeny E.
        • Bongartz G.
        • et al.
        Detection of hepatic masses in patients with carcinoma: comparative sensitivities of sonography, CT, and MR imaging.
        AJR Am J Roentgenol. 1991; 157: 731-739
        • Kuszyk B.S.
        • Bluemke D.A.
        • Urban B.A.
        • et al.
        Portal-phase contrast-enhanced helical CT for the detection of malignant hepatic tumors: sensitivity based on comparison with intraoperative and pathologic findings.
        AJR Am J Roentgenol. 1996; 166: 91-95
        • Niekel M.C.
        • Bipat S.
        • Stoker J.
        Diagnostic imaging of colorectal liver metastases with CT, MR imaging, FDG PET, and/or FDG PET/CT: a meta-analysis of prospective studies including patients who have not previously undergone treatment.
        Radiology. 2010; 257: 674-684
        • Nguyen P.
        • Feng J.C.
        • Chang K.J.
        Endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration (FNA) of liver lesions.
        Gastrointest Endosc. 1999; 50: 357-361
        • Awad S.S.
        • Fagan S.
        • Abudayyeh S.
        • et al.
        Preoperative evaluation of hepatic lesions for the staging of hepatocellular and metastatic liver carcinoma using endoscopic ultrasonography.
        Am J Surg. 2002; 184: 601-604
        • Prasad P.
        • Schmulewitz N.
        • Patel A.
        • et al.
        Detection of occult liver metastases during EUS for staging of malignancies.
        Gastrointest Endosc. 2004; 59: 49-53
        • Singh P.
        • Mukhopadhyay P.
        • Bhatt B.
        • et al.
        Endoscopic ultrasound versus CT scan for detection of the metastases to the liver: results of a prospective comparative study.
        J Clin Gastroenterol. 2009; 43: 367-373
        • Hollerbach S.
        • Willert J.
        • Topalidis T.
        • et al.
        Endoscopic ultrasound-guided fine-needle aspiration biopsy of liver lesions: histological and cytological assessment.
        Endoscopy. 2003; 35: 743-749
        • DeWitt J.
        • LeBlanc J.
        • McHenry L.
        • et al.
        Endoscopic ultrasound-guided fine needle aspiration cytology of solid liver lesions: a large single-center experience.
        Am J Gastroenterol. 2003; 98: 1976-1981
        • Sey M.S.
        • Al-Haddad M.
        • Imperiale T.F.
        • et al.
        EUS-guided liver biopsy for parenchymal disease: a comparison of diagnostic yield between two core biopsy needles.
        Gastrointest Endosc. 2016; 83: 347-352
        • Mohan B.P.
        • Shakhatreh M.
        • Garg R.
        • et al.
        Efficacy and safety of EUS-guided liver biopsy: a systematic review and meta-analysis.
        Gastrointest Endosc. 2019; 89: 238-246
        • Fujii-Lau L.L.
        • Abu Dayyeh B.K.
        • et al.
        EUS-derived criteria for distinguishing benign from malignant metastatic solid hepatic masses.
        Gastrointest Endosc. 2015; 81: 1188-1196
        • Kitano M.
        • Sakamoto H.
        • Matsui U.
        • et al.
        A novel perfusion imaging technique of the pancreas: contrast-enhanced harmonic EUS (with video).
        Gastrointest Endosc. 2008; 67: 141-150
        • Fusaroli P.
        • Napoleon B.
        • Gincul R.
        • et al.
        The clinical impact of ultrasound contrast agents in EUS: a systematic review according to the levels of evidence.
        Gastrointest Endosc. 2016; 84: 587-596
        • Kitano M.
        • Kudo M.
        • Yamao K.
        • et al.
        Characterization of small solid tumors in the pancreas: the value of contrast-enhanced harmonic endoscopic ultrasonography.
        Am J Gastroenterol. 2012; 107: 303-310
        • Omoto S.
        • Takenaka M.
        • Kitano M.
        • et al.
        Characterization of pancreatic tumors with quantitative perfusion analysis in contrast-enhanced harmonic endoscopic ultrasonography.
        Oncology. 2017; 93: 55-60
        • Kamata K.
        • Takenaka M.
        • Omoto S.
        • et al.
        Impact of avascular areas, as measured by contrast-enhanced harmonic EUS, on the accuracy of FNA for pancreatic adenocarcinoma.
        Gastrointest Endosc. 2018; 87: 158-163
        • Kamata K.
        • Takenaka M.
        • Kitano M.
        • et al.
        Contrast-enhanced harmonic endoscopic ultrasonography for differential diagnosis of localized gallbladder lesions.
        Dig Endosc. 2018; 30: 98-106
        • Kamata K.
        • Takenaka M.
        • Kitano M.
        • et al.
        Contrast-enhanced harmonic endoscopic ultrasonography for differential diagnosis of submucosal tumors of the upper gastrointestinal tract.
        J Gastroenterol Hepatol. 2017; 32: 1686-1692
        • Miyata T.
        • Kitano M.
        • Omoto S.
        • et al.
        Contrast-enhanced harmonic endoscopic ultrasonography for assessment of lymph node metastases in pancreatobiliary carcinoma.
        World J Gastroenterol. 2016; 22: 3381-3391
        • Yanagisawa K.
        • Moriyasu F.
        • Miyahara T.
        • et al.
        Phagocytosis of ultrasound contrast agent microbubbles by Kupffer cells.
        Ultrasound Med Biol. 2007; 33: 318-325
        • Watanabe R.
        • Matsumura M.
        • Munemasa T.
        • et al.
        Mechanism of hepatic parenchyma-specific contrast of microbubble-based contrast agent for ultrasonography: microscopic studies in rat liver.
        Invest Radiol. 2007; 42: 643-651
        • Sasaki S.
        • Iijima H.
        • Moriyasu F.
        • et al.
        Definition of contrast enhancement phases of the liver using a perfluoro-based microbubble agent, perflubutane microbubbles.
        Ultrasound Med Biol. 2009; 35: 1819-1827
        • Kudo M.
        • Ueshima K.
        • Osaki Y.
        • et al.
        B-mode ultrasonography versus contrast-enhanced ultrasonography for surveillance of hepatocellular carcinoma: a prospective multicenter randomized controlled trial.
        Liver Cancer. 2019; 8: 271-280
        • Goto E.
        • Masuzaki R.
        • Tateishi R.
        • et al.
        Value of post-vascular phase (Kupffer imaging) by contrast-enhanced ultrasonography using Sonazoid in the detection of hepatocellular carcinoma.
        J Gastroenterol. 2012; 47: 477-485
        • Chang K.J.
        • Samarasena J.B.
        • Iwashita T.
        • et al.
        Endo-hepatology: a new paradigm.
        Gastrointest Endosc Clin N Am. 2012; 22: 379-385
        • Srinivasan I.
        • Tang S.J.
        • Vilmann A.S.
        • et al.
        Hepatic applications of endoscopic ultrasound: current status and future directions.
        World J Gastroenterol. 2015; 21: 12544-12557
        • Campos S.
        • Poley J.W.
        • van Driel L.
        • et al.
        The role of EUS in diagnosis and treatment of liver disorders.
        Endosc Int Open. 2019; 7: E1262-E1275
        • Shiozawa K.
        • Watanabe M.
        • Ikehara T.
        • et al.
        Comparison of contrast-enhanced ultrasonography with Gd-EOB-DTPA-enhanced MRI in the diagnosis of liver metastasis from colorectal cancer.
        J Clin Ultrasound. 2017; 45: 138-144
        • Hiraoka A.
        • Kume M.
        • Miyagawa M.
        • et al.
        Diagnostic value of Sonazoid for hepatic metastasis: comparison with FDG PET/CT.
        Hepatogastroenterology. 2010; 57: 1237-1240
        • Dietrich C.F.
        • Kratzer W.
        • Strobe D.
        • et al.
        Assessment of metastatic liver disease in patients with primary extrahepatic tumors by contrast-enhanced sonography versus CT and MRI.
        World J Gastroenterol. 2006; 12: 1699-1705
        • Kinkel K.
        • Lu Y.
        • Both M.
        • et al.
        Detection of hepatic metastases from cancers of the gastrointestinal tract by using noninvasive imaging methods (US, CT, MR imaging, PET): a meta-analysis.
        Radiology. 2002; 224: 748-756
        • tenBerge J.
        • Hoffman B.J.
        • Hawes R.H.
        • et al.
        EUS-guided fine needle aspiration of the liver: indications, yield, and safety based on an international survey of 167 cases.
        Gastrointest Endosc. 2002; 55: 859-862
        • Bhatia V.
        • Hijioka S.
        • Hara K.
        • et al.
        Endoscopic ultrasound description of liver segmentation and anatomy.
        Dig Endosc. 2014; 26: 482-490
        • Tsujino T.
        • Samarasena J.B.
        • Chang K.J.
        EUS anatomy of the liver segments.
        Endosc Ultrasound. 2018; 7: 246-251
        • Motosugi U.
        • Ichikawa T.
        • Morisaka H.
        • et al.
        Detection of pancreatic carcinoma and liver metastases with gadoxetic acid-enhanced MR imaging: comparison with contrast-enhanced multi-detector row CT.
        Radiology. 2011; 260: 446-453
        • Ito T.
        • Sugiura T.
        • Okamura Y.
        • et al.
        The diagnostic advantage of EOB-MR imaging over CT in the detection of liver metastasis in patients with potentially resectable pancreatic cancer.
        Pancreatology. 2017; 17: 451-456

      Linked Article

      • Kupffer-phase EUS: the contrast agent that magnifies liver metastasis
        Gastrointestinal EndoscopyVol. 93Issue 2
        • Preview
          Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth most common cause of cancer-related death and is projected to become the second most common by 2030.1 Although the only curative treatment is surgical resection, <20% of patients are resectable at diagnosis because most of them have locally advanced or metastatic disease.
        • Full-Text
        • PDF