Early detection and characterization of hepatocellular. Early Detection and Curative Treatment of Early-Stage Hepatocellular Carcinoma

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3:S144 S148 Early Detection and Curative Treatment of Early-Stage MASATOSHI KUDO Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan The method for early detection of hepatocellular carcinoma (HCC) has been well-established in Japan by means of regularly screening patients at risk for developing HCC by using imaging and tumor markers. An important issue is the accurate characterization of nodular lesions found in cirrhotic livers. This problem has been addressed by development of imaging modalities such as ultrasonography angiography with intra-arterial injection of CO 2, computed tomography during hepatic arteriography, and computed tomography during arterial portography. It is most important to differentiate the typical hemodynamic patterns of low-grade dysplastic nodule including arterial hypovascularity with preserved portal perfusion from those of HCC characterized by arterial hypervascularity with decreased portal perfusion. At present, these findings are easily obtained by contrast-enhanced phase-invasion harmonic imaging, which is a noninvasive ultrasound technology. Radiofrequency ablation is an efficient technique to curatively treat early-stage HCC. The 5-year survival rate of RFA at our institution is 76%. Although local recurrence rate after curative RFA is as low as 6.2%, the intrahepatic distant metastasis is as high as 85% at 5 years. The prevention of intrahepatic distant recurrence by maintenance interferon therapy is thus very important. The 5-year survival rate and first, second, and third recurrence rates after curative RFA in patients who had maintenance interferon therapy were much better than those in patients who did not receive interferon therapy after curative RFA. In conclusion, recent progress in screening, diagnostic, and therapeutic strategy for early-stage HCC has improved the prognosis of patients with HCC. Furthermore, advances of prognostic staging system, such as Japan Integrated Staging score, facilitate the management of HCC. Early detection and characterization of hepatocellular carcinoma (HCC) are important in improving prognosis of patients with HCC. To characterize such nodular lesions correctly, evaluation of intranodular hemodynamics is of value, because pathologic findings or malignancy grades of HCC are closely related to intranodular hemodynamics. In addition, curative treatment and prevention of recurrence after curative treatment are other important issues. In this article, the methods for early detection of HCC and its differentiation from premalignant and/or borderline lesions as well as curative treatment including maintenance interferon therapy are described. Early Detection of Hepatocellular Carcinoma In Japan, the screening protocol for early detection of HCC has been established during the past 2 decades. Patients with chronic viral hepatitis/liver cirrhosis caused by HBV or HCV infection are regarded as high risk for developing HCC. Regular follow-up by ultrasonography (US) every 3 months and measurements of tumor markers including alpha-fetoprotein, its activity to bind with Lens culinaris agglutinin A and protein induced by vitamin K absence or antagonist-ii every month, have made it possible to detect HCC in an early stage. However, it has brought about another problematic issue that the more frequently US is performed, the more small nodular lesions are detected in the liver, along with increasingly more lesions not diagnosed as overt HCC. This is a very important problem that needs to be addressed and solved. Differential Diagnosis of Overt, Early Well-Differentiated Hepatocellular Carcinoma, and Low-Grade Dysplastic Nodule Intranodular Hemodynamics of Overt Because afferent blood vessels of an overt HCC are from the hepatic artery, intranodular hemodynamics in Abbreviations used in this paper: CT, computed tomography; CTAP, computed tomography during arterial portography; CTHA, computed tomography during hepatic arteriography; HCC, hepatocellular carcinoma; JIS, Japan Integrated Staging; LGDN, low-grade dysplastic nodule; PEIT, percutaneous ethanol injection; RFA, radiofrequency ablation; US, ultrasonography by the American Gastroenterological Association /05/$30.00 PII: /S (05)

2 October Supplement 2005 EARLY DETECTION AND CURATIVE TREATMENT OF EARLY-STAGE HCC S145 HCC are characterized by arterial neovascularization and absence of portal venous flow. 1,2 In contrast, the hemodynamic pattern of a premalignant lesion (low-grade dysplastic nodule [LGDN]) or a borderline lesion manifests itself with poor arterial vascularity and the presence of portal supply or an increase thereof. 3,4 The imaging diagnosis of HCC and premalignant lesions is based on such characteristics of intranodular hemodynamics. Angiography is not always efficient in demonstrating arterial hypovascularity or portal venous flow in small nodules less than 1.5 cm in diameter, as previously reported. Rather, US angiography and computed tomography during hepatic arteriography (CTHA) are more sensitive in detecting intranodular arterial vascularity. Computed tomography during arterial portography (CTAP) also is a sensitive tool in detecting portal perfusion within a nodule, 5,6 enabling differentiation of overt HCC from a premalignant lesion. Likewise, color Doppler imaging is useful in detecting afferent portal venous flow in premalignant lesions. 7 Recently, contrast-enhanced US with intravenous injection of a contrast agent, Levovist (Schering, Berlin, Germany), has been reported to be useful in evaluating portal perfusion within the nodule, leading to improved differentiation of LGDN from overt HCC Hemodynamics of Well-Differentiated in an Early Stage Most well-differentiated HCCs in an early stage do not stain on angiography or retain iodized oil within the tumor, thereby making the diagnosis difficult. 6 It is also well-known that some well-differentiated HCCs in an early stage are fed by the portal vein, not by the hepatic artery, unlike typical HCCs Therefore, some hypovascular HCCs (early-stage HCCs) show no perfusion defects on CTAP and might look like benign nodules with benign-appearing patterns of the vasculature. 9 Color Doppler imaging also picks up afferent portal flow signals. 7,16 With the exception of these nodules having a benign-appearing hemodynamic pattern, the diagnosis of HCC is possible even in its early stage by a combined use of tomographic vascular imagings, including US angiography, CTHA, and CTAP. 6,13,17 Role of Harmonic Imaging in the Characterization of Hepatocellular Carcinoma and Low-Grade Dysplastic Nodule Detection of Arterial and Portal Flows in Contrast-enhanced harmonic imaging 8,10,11,18 detects intratumoral vascularity in more than 95% of HCCs; no blood signals are observed only in the remaining 5%. Likewise, 98% of HCC nodules show hypervascularity and/or isovascularity on dynamic computed tomography (CT). Therefore, the detection rate of intratumoral vascularity is not different between contrast harmonic US and CT. 8,10 In the hypervascular HCCs, contrast-enhanced harmonic US images tumor vessels originating in the periphery and infiltrating into the center of tumors and having irregular branches. Most HCCs show heterogeneous or homogeneous staining of tumor parenchyma, which is hyperechoic on the gray scale background in comparison with surrounding liver parenchyma. Perfusion defects in the postvascular phase, as a result of fast washout from the nodule, are other characteristics of these HCCs. Low-Grade Dysplastic Nodule Contrast-enhanced harmonic US in the early arterial phase depicts no blood vessels in any LGDNs. In the late vascular phase and postvascular phase, it can detect isovascular staining in 75% and hypervascular staining in 12.5% of them, pointing to a portal venous supply in them. The sensitivity and specificity of LGDN pattern are 75% and 100%, respectively, with the positive and negative predictive values of 100% and 99%, respectively. In contrast, dynamic CT images low attenuation only in the arterial phase in all the dysplastic nodules; it is accompanied by isoattenuation in the portal and delayed phase in 75% of LGDNs. Therefore, the rate of detecting intranodular vascularity in LGDNs is comparable between contrastenhanced harmonic US and dynamic CT. 8,10 Recently, pure arterial phase imaging, a novel contrast US technique, clearly showed portal venous flow within the LGDN, which is proved by CTAP. Radiofrequency Ablation Radiofrequency ablation (RFA) is a new therapeutic technique in which dielectric heating caused by radiofrequency waves (460 5 Hz) in the region around the electrode inserted in a lesion almost fully coagulates and necrotizes liver tumors. RFA uses an expandable or cool-tip electrode needle, and single coagulation is able to necrotize a total area of about 3 4 cm. Accordingly, curative ablation for a tumor measuring 3.0 cm or less can be completed with a single treatment session. The current indications are 3 or fewer tumors measuring 3 cm or less or a solitary tumor with a major axis of 5 cm or less. Because local occlusion of hepatic blood flow, by using a balloon or transcatheter arterial embolization, increases the coagulated area in RFA, this combination has been used successfully.

3 S146 MASATOSHI KUDO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 10 local controllability. 19,21,23 Livraghi et al 24 performed a prospective study and found that a complete response was obtained in 90% by RFA and in 80% by PEIT in patients with liver cancers smaller than 3 cm. The number of sessions of RFA was 1.2, whereas that of PEIT was 4.8. However, the frequency of complications was slightly higher with RFA than with PEIT. Shiina et al 21 compared RFA and PEIT in a prospective randomized controlled trial in patients with 3 or fewer liver cancers smaller than 3 cm. RFA was superior to PEIT in the 4-year survival rate (74% vs 57%), overall recurrence rate (70% vs 85%), and local recurrence rate (1.7% vs 11%). Figure 1. Cumulative survival rate after curative RFA. The local recurrence rate after RFA varied from 1.7% 14% In our series of 137 patients with HCC who underwent curative RFA therapy (Figure 1), local recurrence was observed in 9 cases (local recurrence rate, 10 of 161 nodules or 6.2%), whereas cumulative local recurrence rate, calculated by Kaplan-Meier methods, was 12% at 5 years (Figure 2). The rate might have depended on the size of nodules treated and the skill of the operators. The risk of local recurrence increases with increase in size, but the local recurrence rate differs markedly depending on whether a circumferential 5-mm safety margin is secured. When the indication was limited to nodules smaller than 3 cm, 90% or more necrosis was obtained in many cases, whereas the therapeutic results were poor for nodules larger than 3 cm but smaller than 5cm. 20,22 In a prospective controlled study of percutaneous ethanol injection (PEIT) and RFA, RFA was superior to PEIT in Maintenance Interferon Therapy After Curative Ablation of Because intrahepatic distant metastasis is as high as 85% at 5 years after curative RFA (Figure 2), it is extremely important to improve the prognosis of patients who have undergone local ablation therapy by treating baseline liver disease by using chemopreventive drugs such as interferon. Several studies in which interferon was used after curative local treatment documented that interferon was useful for the prevention of recurrence after treatment Our experience also supported such data, ie, that interferon does delay the period to clinical recurrence after curative ablation by RFA (Figure 3), resulting in improved disease-controlled survival and better overall survival (Figure 4). It is understood that interferon prevents the multifocal recurrence through the suppression of inflammation, but it is still unknown whether interferon suppresses the growth of intrahepatic metastasis. Our results seem to suggest the latter possi- Figure 2. Recurrence rates after curative RFA.

October Supplement 2005 EARLY DETECTION AND CURATIVE TREATMENT OF EARLY-STAGE HCC S147 Figure 3. Cumulative first recurrence rates after RFA. IFN, interferon.

4 October Supplement 2005 EARLY DETECTION AND CURATIVE TREATMENT OF EARLY-STAGE HCC S147 Figure 3. Cumulative first recurrence rates after RFA. IFN, interferon. bility, because early recurrence immediately after RFA was suppressed, whereas, in contrast, later recurrence was not suppressed so much. 27 Prognostic Staging System for A prognostic staging system is very important in the prediction of prognosis, selection of treatment modality, or comparison of treatment method. The Japan Integrated Staging ( JIS) score was initially proposed by Kudo et al 28,29 and is regarded as one of the most frequently used staging systems. 30,31 The JIS score is obtained by simply adding both scores for the TNM stage by LCSGJ (Liver Cancer Study Group of Japan) and Child-Turcotte-Pugh stage. Scores for the TNM stage can be easily obtained by allocating stages I, II, III, and IV to scores 0, 1, 2, and 3, respectively. Scores for Child-Turcotte-Pugh stage can be similarly obtained by allocating Child-Turcotte-Pugh A, B, and C to scores 0, 1, and 2, respectively. Fairly good stratification was obtained from scores 0 5 by JIS score compared with CLIP (Cancer of the Liver Italian Program) score, which cannot discriminate advanced stage HCC (CLIP score, 4 6). Furthermore, patient distribution in each JIS score was much better than that in the corresponding CLIP scores. As a consequence of these favorable characteristics, the long-term survival rate of the best prognostic subgroup in JIS score is extremely high. Furthermore, the worst prognostic subgroup ( JIS score 5) was accurately identified by this staging system. This was not possible in CLIP score as described in the previous literature. 30 Therefore, the JIS score can correctly identify the patient subgroup from early, intermediate, advanced, and end-stage HCC patient subgroups, which greatly benefits clinical hepatology. The ultimate condition for the primary staging system for HCC is clinical staging, which can be applied to all patients from early stage to end stage; in light of this, the JIS scoring system would be of great value as a prognostic staging system. Thus, it might be used as an international standard scale when comparing the treatment results among several modalities, institutions, or countries, or when testing the effectiveness of a new treatment method for HCC. Conclusion Early detection of HCC and accurate characterization of nodular lesions in cirrhotic livers are equally important. Therefore, it is of utmost importance to clearly detect intranodular hemodynamic alterations during multistep human hepatocarcinogenesis by imaging intranodular hemodynamics precisely with use of invasive techniques including CO 2 US, CTHA, and CTAP. Recent remarkable progress in contrast-enhanced harmonic imaging has made it possible to determine the malignant grade with high sensitivity by this noninvasive method. RFA and mainte- Figure 4. Disease-controlled survival rates at 5 years. IFN, interferon.

5 S148 MASATOSHI KUDO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 10 nance interferon therapy are useful in improving the prognosis of patients with HCC. Finally, JIS score clearly facilitates the management of HCC patients. References 1. Nakashima T, Kojiro M. Angioarchitecture of hepatocellular carcinoma. In: Nakashima T, Kojiro M (eds). Hepatocellular carcinoma: an atlas of its pathology. 1st ed. Tokyo: Springer, 1997: Sasaki K. Adenomatous hyperplasia in liver cirrhosis: an approach from a microangiographical point of view. Gann Monogr Cancer Res 1980;25: Takayasu K, Muramatsu Y, Mizuguchi Y, et al. Imaging of early hepatocellular carcinoma and adenomatous hyperplasia (dysplastic nodules) with dynamic CT and a combination of CT and angiography: experience with resected liver specimens. Intervirology 2004;47: Matsui O. Imaging of multistep human hepatocarcinogenesis by CT during intra-arterial contrast injection. Intervirology 2004;47: Matsui O, Kadoya M, Suzuki M, et al. Work in progress: dynamic sequential computed tomography during arterial portography in the detection of hepatic neoplasms. Radiology 1983;146: Kudo M. Imaging diagnosis of hepatocellular carcinoma and premalignant/borderline lesions. Semin Liver Dis 1999;19: Tochio H, Kudo M. Afferent and efferent vessels of premalignant and overt hepatocellular carcinoma: observation by color Doppler imaging. Intervirology 2004;47: Kudo M. Contrast harmonic imaging in the diagnosis and treatment of hepatic tumors. Tokyo: Springer, Kudo M. Atypical large well-differentiated hepatocellular carcinoma with benign nature: a new clinical entity. Intervirology 2004; 47: Wen YL, Kudo M, Zheng RQ, et al. Characterization of hepatic tumors: value of contrast-enhanced coded phase-inversion harmonic angio. AJR Am J Roentgenol 2004;182: Wen YL, Zhou P, Kudo M. Detection of intratumoral vascularity in small hepatocellular carcinoma by coded phase inversion harmonics. Intervirology 2004;47: Choi BI, Lee JY, Han JK, et al. Contrast-enhanced sonography for hepatocellular carcinoma. Intervirology 2004;47: Matsui O, Kadoya M, Kameyama T, et al.: Benign and malignant nodules in cirrhotic livers: distinction based on blood supply. Radiology 1991;178: Kudo M, Tomita S, Tochio H,et al. Sonography with intraarterial infusion of carbon dioxide microbubbles (sonographic angiography): value in differential diagnosis of hepatic tumors. AJR Am J Roentgenol 1992;158: Kudo M, Tomita S, Tochio H, et al. Small hepatocellular carcinoma: diagnosis with US angiography with intraarterial CO2 microbubbles. Radiology 1992;182: Kudo M, Tochio H, Zhou P. Differentiation of hepatic tumors by color Doppler imaging: role of the maximum velocity and the pulsatility index of the intratumoral blood flow signal. Intervirology 2004;47: Kudo M. Morphological diagnosis of hepatocellular carcinoma: special emphasis on intranodular hemodynamic imaging. Hepatogastroenterology 1998;45(Suppl 3): Minami Y, Kudo M, Kawasaki T, et al. Transcatheter arterial chemoembolization of hepatocellular carcinoma: usefulness of coded phase-inversion harmonic sonography. AJR Am J Roentgenol 2003;180: Lencioni RA, Allgaier HP, Cioni D, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 2003:228: Kudo M. Local ablation therapy for hepatocellular carcinoma: current status and future perspectives. Gastroenterology 2004; 39: Shiina S, Teratani T, Obi S, et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 2005;129: Livraghi T, Goldberg SN, Lazzaroni S, et al: Hepatocellular carcinoma: radio-frequency ablation of medium and large lesions. Radiology 2000;214: Lin SM, Lin CT, Lin CC, et al. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma 4cm. Gastroenterology 2004;127: Livraghi T, Goldberg SN, Lazzaroni S, et al. Small hepatocellular carinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology 1999;210: Ikeda K, Arase Y, Saitoh S, et al. Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor: a prospective randomized study of hepatitis C virus-related liver cancer. Hepatology 2000;32: Shiratori Y, Shiina S, Teratani T, et al. Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med 2003;138: Sakaguchi Y, Kudo M, Fukunaga T, et al. Low-dose, long-term, intermittent interferon-alpha 2b therapy after radical treatment by radiofrequency ablation delays clinical recurrence in patients with hepatitis C virus related hepatocellular carcinoma. Intervirology 2005;48: Kudo M, Chung H, Osaki Y. Prognostic staging system for hepatocellular carcinoma (CLIP score): value, limitation and a proposal of new prognostic system, Japan Integrated Staging Score ( JIS Score). J Gastroenterol 2003;38: Kudo M, Chung H, Haji S, et al. Validation of a new prognostic staging system for hepatocellular carcinoma, the JIS score as compared with CLIPscore. Hepatology 2004;40: Wildi S, Pestalozzi BC, McCormack L, et al. Critical evaluation of the different staging system for hepatocellular carcinoma. Br J Surg 2004;91: Marrero JA, Fontana RJ, Barrat A, et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging system in an American cohort. Hepatology 2005;41: Address requests for reprints to: Masatoshi Kudo, MD, Department of Gastroenterology and Hepatology, Kinki University School of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, , Japan. m-kudo@med.kindai.ac.jp; fax:

Detection and Characterization of Hepatocellular Carcinoma by Imaging

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3:S136 S140 Detection and Characterization of Hepatocellular Carcinoma by Imaging OSAMU MATSUI Department of Imaging Diagnosis and Interventional Radiology,