Contrast-enhanced US with Sulfur Hexafluoride and Perfluorobutane for the Diagnosis of Hepatocellular Carcinoma in Individuals with High Risk
Authors: Hyo-Jin Kang, Jeong Min Lee , Jeong Hee Yoon, Kyoungbun Lee, Haeryoung Kim, Joon Koo Han
Journal: . Radiology. 2020 Aug 4
DOI: doi.org/10.1148/radiol.2020200115
Dr. Ivo Sá Marques, Resident, Department of Medical Imaging, Coimbra Hospital and University Centre, Coimbra (Portugal).
Dr. Daniel Ramos Andrade, Radiology Consultant, Coimbra Hospital and University Centre, Coimbra (Portugal).
Prof. Dr. Luís Curvo Semedo, Radiology Consultant, Coimbra Hospital and University Centre; Assistant Professor, Faculty of Medicine - University of Coimbra (Portugal).
Contrast ultrasound (CEUS) is increasingly used in the liver given its high accuracy in the differential diagnosis of focal liver lesions. This technique is readily available, cost-effective and has almost no contraindications and adverse events. Its disadvantages are closely related to the ultrasound technique itself. The ultrasound contrast agent available in Europe - sulphur hexafluoride (SHF) consists of sulphur hexafluoride microbubbles coated with phospholipids, with a diameter of <10 μm that remain strictly intravascular, with no diffusion into the interstice. [2]
Perfluorobutane (PFB) is a contrast agent that contains perfluorobutane microbubbles inside a phosphatidylserine shell (diameter 2–3 μm). They reach the liver in about 15 s, allowing imaging of the hepatic arterial vascularization and are also captured by Kupffer cells in the reticuloendothelial system of the liver, which enables parenchyma-specific liver imaging. This Kupffer phase imaging is generally performed 10 minutes after intravenous contrast media administration, at which time the normal hepatic parenchyma is enhanced. Therefore, malignant lesions containing few or no Kupffer cells are clearly shown as contrast defects in this phase. An advantage of PFB microbubbles over SHF is their ability to resonate with moderate ultrasound pressure without collapsing, which facilitates the scanning of the entire liver in a Kupffer phase for several hours. [3,4]
In this article, Kang et al. compared the enhancement patterns and diagnostic performance of CEUS with PFB and SHF, in the characterization of liver nodules in patients with a high probability of HCC, based on the CEUS Liver Image Reporting and Data System (LI-RADS®) of the American College of Radiology (ACR). CEUS LI-RADS® standardizes the CEUS technique, interpretation, reporting and data collection for patients at risk of developing hepatocellular carcinoma (HCC). [5]
The study included, from February to August 2019, patients older than 18 years old, at risk of HCC, with one or more treatment-naive hepatic observations (>1 cm) of LR -3, LR-4, LR-5 or LR-M according to CT / MRI LI-RADS version 2018 in acceptable diagnostic images obtained 6 weeks before enrolment. Patients with congestive liver disease, an obvious tumour in a vein and severe cardiovascular dysfunction were excluded. First, an operator radiologist studied the observations with the US-SHF and, soon after the degradation of the microbubbles with high mechanical index pulses in B-mode, the study with PFB proceeded with an interval of at least 30 minutes. The dynamic imaging characteristics (arterial phase hyperenhancement, washout time and degree, and echogenicity in the Kupffer phase) were recorded and then later observed by a reviewer. Only LR-5 observations were assumed to be diagnostic of HCC.
43 of the 59 included observations were confirmed as HCCs. Specificity was 100% for both types of contrast-enhanced US exams. PFB-enhanced US provided higher sensitivity (79% and 74%) and accuracy 0.90 and 0.87 for HCC diagnosis compared with SHF-enhanced US (sensitivity, 54% and 58%; p = .01 and p = .048; accuracy, 0.77 and 0.79, p = .01 and p = .04, for the operator and reviewer, respectively) with implementation of diagnostic criteria for CEUS LI-RADS.
Despite most of the malignancies manifesting clear hypoenhancement in the Kupffer phase with PFB, the degree and prevalence of hypoenhancement did not differ between HCCs and non-HCC malignancies, so the Kupffer phase, in isolation, has no increased specificity. However, reassuringly, none of the benign lesions had hypoenhancement in this phase. These findings suggest we can get a more confident diagnosis of malignancy with the Kupffer phase of PFB.
A possible explanation by the authors for the marginally better results of PFB is that high acoustic pressure, which offers higher spatial resolution, may contribute to improved lesion-to-parenchymal echogenicity differences during the late phase, and thus increase the sensitivity.
As stated by their authors, this study has some limitations. In addition to having a small population of a single centre, the biggest constraint could be the fact that both CEUS examinations were performed by one operator per participant with short intervals between them and after CT / MR pre-selection observations, which could produce a selection bias and affect the diagnostic performance of the CEUS.
In conclusion, even for the most critical, CEUS is a technique that might be useful in the future. For the follow-up of suspicious HCC nodules, it has economic and security advantages. It’s doubtful if PFB will be able to replace SHF in the characterization of suspicious HCC nodules. In theory, PFB has advantages over SHF in lesion-to-parenchymal contrast, however, the importance of the Kupffer phase in isolation remains to be seen.
References
- Kang HJ, Lee JM, Yoon JH, Lee K, Kim H, Han JK. Contrast-enhanced US with Sulfur Hexafluoride and Perfluorobutane for the Diagnosis of Hepatocellular Carcinoma in Individuals with High Risk. Radiology. 2020 Oct; 297(1):E24 doi: 10.1148/radiol.2020209017.
- Schellhaas B, Strobel D. Tips and Tricks in Contrast-Enhanced Ultrasound (CEUS) for the Characterization and Detection of Liver Malignancies. Ultraschall Med. 2019 Aug;40(4):404-424. English. doi: 10.1055/a-0900-396
- Park HS, Kim YJ, Yu MH, Jung SI, Jeon HJ. Real-time contrast-enhanced sonographically guided biopsy or radiofrequency ablation of focal liver lesions using perflurobutane microbubbles (sonazoid): value of Kupffer-phase imaging. J Ultrasound Med. 2015 Mar;34(3):411-21. doi: 10.7863/ultra.34.411
- Goto E, Masuzaki R, Tateishi R, Kondo Y, Imamura J, Goto T, Ikeda H, Akahane M, Shiina S, Omata M, Yoshida H, Koike K. Value of post-vascular phase (Kupffer imaging) by contrast-enhanced ultrasonography using Sonazoid in the detection of hepatocellular carcinoma. J Gastroenterol. 2012 Apr;47(4):477-85. doi: 10.1007/s00535-011-0512-9
- Kono Y, Lyshchik A, Cosgrove D, Dietrich CF, Jang HJ, Kim TK, Piscaglia F, Willmann JK, Wilson SR, Santillan C, Kambadakone A, Mitchell D, Vezeridis A, Sirlin CB. Contrast Enhanced Ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS®): the official version by the American College of Radiology (ACR). Ultraschall Med. 2017 Jan;38(1):85-86. doi: 10.1055/s-0042-124369.
Dr. Ivo Sá Marques is a second-year resident of Radiology at the Centro Hospitalar e Universitário de Coimbra, Portugal. He started his medical course at Nova Medical School in Lisbon and completed it at the Faculdade de Medicina da Universidade do Porto. He is author of several national papers and was a speaker at the 2019 Portuguese Radiology Society Conference. His main interests in diagnostic radiology are abdomen and trauma.
Comments may be sent to sa.marques.ivo@gmail.com