Safety margin of radiofrequency ablation for hepatocellular carcinoma: a prospective study using magnetic resonance imaging with superparamagnetic iron oxide

  • Kuniaki FukudaEmail author
  • Kensaku Mori
  • Naoyuki Hasegawa
  • Katsuhiro Nasu
  • Kazunori Ishige
  • Yoshikazu Okamoto
  • Masanari Shiigai
  • Masato Abei
  • Manabu Minami
  • Ichinosuke Hyodo
Original Article



In radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC), it is difficult to assess the ablative margin (AM) precisely by comparing pre- and post-RFA CT images. We prospectively studied the AMs using magnetic resonance imaging (MRI) with pre-administered superparamagnetic iron oxide (SPIO). SPIO is safe for kidney disease patients.

Materials and methods

Hepatocellular carcinoma patients were treated with RFA within 8 h of SPIO administration. On T2*-weighted MRI performed 4–7 days later, AM was visualized as a hypointense rim. The ablation status was classified as AM(+) if the rim completely surrounded the tumor, AM(0) if the rim was partly discontinuous without tumor protrusion, and AM(−) if the rim was partly discontinuous with tumor protrusion. The minimal thickness of AM was measured. AM(−) tumors were re-treated consecutively.


In total, 85 HCCs ablated in 76 patients were evaluated. The local recurrence rate at 3 years was 2% for AM(+) tumors and 34% for AM(0) tumors (p < 0.01). In addition, no local recurrence was seen in the tumors with an AM of ≥ 2 mm.


MRI with pre-administered SPIO is useful for determining the AM precisely, and an AM of ≥ 2 mm is recommended for curative RFA.

Trial registration number

This study was registered with UMIN Clinical Trials Registry (UMIN 000025406).


Hepatocellular carcinoma Radiofrequency ablation Superparamagnetic iron oxide Ablative margin 


Author contribution

KM and KF contributed equally. Study concepts, data analysis and manuscript drafting: KF and KM; acquisition of data and clinical studies: all authors; statistical analysis: NH; critical revision of the manuscript for important intellectual content: MA, MM, and IH; manuscript editing and final approval: all authors.


This study was not supported by any grants.

Compliance with ethical standards

Conflict of interest

All authors declare no potential conflict of interest.

Ethical statement

This study was approved by the institutional ethics committee (H19-208) and was conducted in accordance with the ethical standards of the Declaration of Helsinki.


  1. 1.
    Cho YK, Rhim H, Noh S. Radiofrequency ablation versus surgical resection as primary treatment of hepatocellular carcinoma meeting the Milan criteria: a systematic review. J Gastroenterol Hepatol. 2011;26:1354–60.Google Scholar
  2. 2.
    Livraghi T, Meloni F, Di Stasi M, Rolle E, Solbiati L, Tinelli C, et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: is resection still the treatment of choice? Hepatology. 2008;47:82–9.CrossRefGoogle Scholar
  3. 3.
    Feng K, Yan J, Li X, Xia F, Ma K, Wang S, et al. A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma. J Hepatol. 2012;57:794–802.CrossRefGoogle Scholar
  4. 4.
    Chen MS, Li JQ, Zheng Y, Guo RP, Liang HH, Zhang YQ, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg. 2006;243:321–8.CrossRefGoogle Scholar
  5. 5.
    Nakazawa T, Kokubu S, Shibuya A, Ono K, Watanabe M, Hidaka H, et al. Radiofrequency ablation of hepatocellular carcinoma: correlation between local tumor progression after ablation and ablative margin. Am J Roentgenol. 2007;188:480–8.CrossRefGoogle Scholar
  6. 6.
    Mori K, Fukuda K, Asaoka H, Ueda T, Kunimatsu A, Okamoto Y, et al. Radiofrequency ablation of the liver: determination of ablative margin at MR imaging with impaired clearance of ferucarbotran-feasibility study. Radiology. 2009;251:557–65.CrossRefGoogle Scholar
  7. 7.
    Hamm B, Staks T, Taupitz M, et al. Contrast-enhanced MR imaging of liver and spleen: first experience in humans with a new superparamagnetic iron oxide. J Magn Reson Imaging. 1994;4:659–68.CrossRefGoogle Scholar
  8. 8.
    Mori K, Takahashi N, Hiratsuka M, Shiigai M, Minami M, Oda T, et al. Detection of hepatic metastases using ferucarbotran-enhanced MR imaging: feasibility and diagnostic accuracy of three-dimensional sensitivity-encoding water-excitation multishot echo-planar sequence (3D-SWEEP). J Magn Reson Imaging. 2006;24:1110–6.CrossRefGoogle Scholar
  9. 9.
    Sasaki A, Kai S, Iwashita Y, Hirano S, Ohta M, Kitano S. Microsatellite distribution and indication for locoregional therapy in small hepatocellular carcinoma. Cancer. 2005;103:299–306.CrossRefGoogle Scholar
  10. 10.
    Ochiai T, Takayama T, Inoue K, Yamamoto J, Shimada K, Kosuge T, et al. Hepatic resection with and without surgical margins for hepatocellular carcinoma in patients with impaired liver function. Hepatogastroenterology. 1999;46:1885–9.Google Scholar
  11. 11.
    Lee JW, Lee YJ, Park KM, Hwang DW, Lee JH, Song KB. Anatomical resection but not surgical margin width influence survival following resection for HCC, a propensity score analysis. World J Surg. 2016;40:1429–39.CrossRefGoogle Scholar
  12. 12.
    Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362:1907–17.CrossRefGoogle Scholar
  13. 13.
    Koda M, Tokunaga S, Miyoshi K, Kishina M, Fujise Y, Kato J, et al. Ablative margin states by magnetic resonance imaging with ferucarbotran in radiofrequency ablation for hepatocellular carcinoma can predict local tumor progression. J Gastroenterol. 2013;48:1283–92.CrossRefGoogle Scholar
  14. 14.
    Shibata T, Isoda H, Hirokawa Y, Arizono S, Shimada K, Togashi K. Small hepatocellular carcinoma: is radiofrequency ablation combined with transcatheter arterial chemoembolization more effective than radiofrequency ablation alone for treatment? Radiology. 2009;252:905–13.CrossRefGoogle Scholar
  15. 15.
    Tomonari A, Tsuji K, Yamazaki H, Aoki H, Kang JH, Kodama Y, et al. Feasibility of fused imaging for the evaluation of radiofrequency ablative margin for hepatocellular carcinoma. Hepatol Res. 2013;43:728–34.CrossRefGoogle Scholar
  16. 16.
    Tang H, Tang Y, Hong J, Chen T, Mai C, Jiang P. A measure to assess the ablative margin using 3D-CT image fusion after radiofrequency ablation of hepatocellular carcinoma. HPB. 2015;17:318–25.CrossRefGoogle Scholar
  17. 17.
    Wang XL, Li K, Su ZZ, Huang ZP, Wang P, Zheng RQ. Assessment of radiofrequency ablation margin by MRI-MRI image fusion in hepatocellular carcinoma. World J Gastroenterol. 2015;21:5345–51.CrossRefGoogle Scholar
  18. 18.
    Nishigaki Y, Hayashi H, Tomita E, Suzuki Y, Watanabe N, Watanabe S, et al. Usefulness of contrast-enhanced ultrasonography using Sonazoid for the assessment of therapeutic response to percutaneous radiofrequency ablation for hepatocellular carcinoma. Hepatol Res. 2015;45:432–40.CrossRefGoogle Scholar
  19. 19.
    Koda M, Tokunaga S, Okamoto T, Hodozuka M, Miyoshi K, Kishina M, et al. Clinical usefulness of the ablative margin assessed by magnetic resonance imaging with Gd-EOB-DTPA for radiofrequency ablation of hepatocellular carcinoma. J Hepatol. 2015;63:1360–7.CrossRefGoogle Scholar
  20. 20.
    Saxton RE, Huang A, Anzai Y, Castro DJ, Lufkin RB. Laser photothermal effects on stability and toxicity of magnetic resonance contrast agents. J Clin Laser Med Surg. 1995;13:363–6.CrossRefGoogle Scholar
  21. 21.
    Merkle EM, Goldberg SN, Boll DT, Shankaranarayanan A, Boaz T, Jacobs GH, et al. Effects of superparamagnetic iron oxide on radiofrequency-induced temperature distribution: in vitro measurements in polyacrylamide phantoms and in vitro results in a rabbit liver model. Radiology. 1999;212:459–66.CrossRefGoogle Scholar
  22. 22.
    Kakite S, Fujii S, Nakamatsu S, Kanasaki Y, Yamashita E, Matsusue E, et al. Usefulness of administration of SPIO prior to RF ablation for evaluation of the therapeutic effect: an experimental study using miniature pigs. Eur J Radiol. 2011;78:282–6.CrossRefGoogle Scholar
  23. 23.
    Nagai M, Yamaguchi M, Mori K, Furuta T, Ashino H, Kurosawa H, et al. Magnetic resonance-based visualization of thermal ablative margins around hepatic tumors by means of systemic ferucarbotran administration before radiofrequency ablation: animal study to reveal the connection between excess iron deposition and T2*-weighted hypointensity in ablative margins. Invest Radiol. 2015;50:376–83.CrossRefGoogle Scholar
  24. 24.
    Nayak AB, Luhar A, Hanudel M, Gales B, Hall TR, Finn JP, et al. High-resolution, whole-body vascular imaging with ferumoxytol as an alternative to gadolinium agents in a pediatric chronic kidney disease cohort. Pediatr Nephrol. 2015;30:515–21.CrossRefGoogle Scholar
  25. 25.
    Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology. 2008;48:2064–77.CrossRefGoogle Scholar
  26. 26.
    D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44:217–31.CrossRefGoogle Scholar
  27. 27.
    Mikami S, Tateishi R, Akahane M, Asaoka Y, Kondo Y, Goto T, et al. Computed tomography follow-up for the detection of hepatocellular carcinoma recurrence after initial radiofrequency ablation: a single-center experience. J Vasc Interv Radiol. 2012;23(10):1269–75.CrossRefGoogle Scholar
  28. 28.
    Zhou P, Kudo M, Minami Y, Chung H, Inoue T, Fukunaga T, Maekawa K. What is the best time to evaluate treatment response after radiofrequency ablation of hepatocellular carcinoma using contrast-enhanced sonography? Oncology. 2007;72(Suppl 1):92–7.CrossRefGoogle Scholar
  29. 29.
    Watanabe H, Kanematsu M, Goshima S, Yoshida M, Kawada H, Kondo H, Moriyama N. Is gadoxetate disodium-enhanced MRI useful for detecting local recurrence of hepatocellular carcinoma after radiofrequency ablation therapy? AJR Am J Roentgenol. 2012;198(3):589–95.CrossRefGoogle Scholar
  30. 30.
    Midorikawa Y, Takayama T, Shimada K, Nakayama H, Higaki T, Moriguchi M, et al. Marginal survival benefit in the treatment of early hepatocellular carcinoma. J Hepatol. 2013;58:306–11.CrossRefGoogle Scholar
  31. 31.
    Li YW, Chen ZG, Wang JC, Zhang ZM. Superparamagnetic iron oxide-enhanced magnetic resonance imaging for focal hepatic lesions: systematic review and meta-analysis. World J Gastroenterol. 2015;21:4334–44.CrossRefGoogle Scholar

Copyright information

© Japan Radiological Society 2019

Authors and Affiliations

  • Kuniaki Fukuda
    • 1
    Email author
  • Kensaku Mori
    • 2
  • Naoyuki Hasegawa
    • 1
  • Katsuhiro Nasu
    • 2
  • Kazunori Ishige
    • 1
  • Yoshikazu Okamoto
    • 2
  • Masanari Shiigai
    • 3
  • Masato Abei
    • 1
  • Manabu Minami
    • 2
  • Ichinosuke Hyodo
    • 1
  1. 1.Department of Gastroenterology, Institute of Clinical Medicine, Faculty of MedicineUniversity of TsukubaTsukubaJapan
  2. 2.Department of Radiology, Faculty of MedicineUniversity of TsukubaIbarakiJapan
  3. 3.Department of RadiologyTsukuba Medical Center HospitalIbarakiJapan

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