Chapter 2: Diagnosis and surveillance

Abstract

Hepatology ResearchVolume 40, Issue s1 p. 16-47 Free Access Chapter 2: Diagnosis and surveillance First published: 19 May 2010 https://doi.org/10.1111/j.1872-034X.2010.00655.xCitations: 5AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat SECTION 1. SURVEILLANCE INTRODUCTION IN THE SURVEILLANCE for hepatocellular carcinoma in patients with chronic liver disease or cirrhosis, ultrasonography and tumor marker tests play central roles and are widely performed at present. In order to demonstrate the efficacy of surveillance, it is necessary to show that early detection increases the opportunity for receiving radical treatment and that it contributes to improvement of the prognosis. Currently, however, there is insufficient evidence to suggest that surveillance by ultrasonography and tumor marker tests undertaken in combination improves the prognosis of patients with hepatocellular carcinoma. Moreover, the positioning and usefulness of computed tomography (CT) or magnetic resonance imaging (MRI) in surveillance for hepatocellular carcinoma also remains unclarified. The optimum intervals for conducting ultrasonography and tumor marker tests should be determined taking into consideration the risk of carcinogenesis in the patients, the costs and other relevant factors; however, there is insufficient evidence relating to the cost–benefit of screening tests. There are reports of randomized controlled trials (RCT) performed to investigate the efficacy of surveillance, but it is ethically difficult to conduct an RCT for reevaluating the results. Under these circumstances, we first attempt to identify “subjects with risk factors for hepatocellular carcinoma” and then try and suggest the appropriate method and interval for hepatocellular carcinoma surveillance based on currently available evidence. SELECTION OF REFERENCES We prepared a list of references on “tumor marker” and “diagnostic imaging (e.g. ultrasonography, CT, MRI and angiography)” listed in MEDLINE and Japana Centra Revuo Medicina from 1982–2002 (MEDLINE and Japana Centra Revuo Medicina, respectively: tumor marker, 1129 and 1179; ultrasonography, 1022 and 1013 articles; diagnostic imaging (other than ultrasonography), 937 and 1550 articles). We read the abstracts of these articles, extracted the published work that seemed to be relevant and useful for surveillance and diagnostic imaging, read the original articles, and finally selected articles, mainly English-language articles providing high-level evidence. For this second version, we extracted articles related to surveillance and diagnostic imaging for hepatocellular carcinoma published between 2003 and June 2007, again read the original articles, and finally selected articles, mainly those providing high-level evidence. CQ4 In what patient subsets should regular hepatocellular carcinoma screening be performed? RECOMMENDATION The risk factors for hepatocellular carcinoma are cirrhosis, chronic hepatitis C, chronic hepatitis B, male sex, advanced age, habitual alcohol consumption, obesity and diabetes mellitus. Among these, regular hepatocellular carcinoma screening is recommended in patients with type C chronic liver disease, type B chronic liver disease or non-viral cirrhosis. (grade B) BACKGROUND Hepatocellular carcinoma is a cancer that has been observed to show marked regional clustering. Hepatitis B virus (HBV) and hepatitis C virus (HCV), and also several environmental factors, are considered to have a great impact on the risk of development of hepatocellular carcinoma. In Japan, approximately 85% of hepatocellular carcinoma patients have underlying type B or C chronic liver disease (Report of the 17th Nationwide Follow-up Survey of Primary Liver Cancer in Japan). Besides these virus-related factors, male sex, advanced age, heavy alcohol consumption, smoking, aflatoxin, obesity and diabetes mellitus have been reported as risk factors for development of liver cancer. These risk factors for hepatocellular carcinoma are discussed in further detail below. SCIENTIFIC STATEMENT Persistent HBV infection is the most significant risk factor for development of liver cancer. HBV carriers have a 223-fold higher risk of carcinogenesis than non-carriers (LF072091 level 2a). Among HBV carriers, HBe antigen-positive persons are at a higher risk for carcinogenesis than HBe antigen-negative persons (relative risk: 6.3 times) (LF072052 level 3, LF038253 level 2a, LF072084 level 3, LF072065 level 3, LF038776 level 3, LF071987 level 3, LF071998 level 2a). Among the patients with type B chronic liver disease, those with cirrhosis are at higher risk. Persistent HCV infection is also as significant a risk factor for carcinogenesis as persistent HBV infection. Particularly in some developed countries, including Japan, it is the most common predisposing factor for development of liver cancer (LF072029 level 4). A characteristic feature of carcinogenesis attributable to hepatitis C is that liver cancer develops against a background of cirrhosis in the majority of cases (LF0357510 level 2a, LF0240411 level 2b). The annual incidence of HCV-related cirrhosis is extremely high, approximately 3–8%, although it varies among countries. Cirrhosis remains a risk factor for development of liver cancer, even in patients who test negative for both HBV and HCV. In patients with primary biliary cirrhosis (PBC), a higher risk of carcinogenesis is noted in Scheuer's stage III or IV, but development of liver cancer is quite rare in stage I or II of the disease (LF0363312 level 2a, LF0716713 level 2a). Based on statistical data from foreign countries, it is evident that hepatocellular carcinoma more commonly affects men. This predilection for men may be related to the differences in factors, such as the prevalence of hepatitis, level of alcohol consumption and androgen levels. Numerous reports have been published to suggest that heavy alcohol consumption and alcoholic liver cirrhosis are risk factors for development of liver cancer; however, questions as to whether the risk is quantity-dependent or there is a threshold have not yet been resolved (LF0720714 level 3, LF0720415 level 3, LF0720316 level 3, LF0719317 level 3, LF0719418 level 3). In addition, alcohol also increases the risk of development of liver cancer in patients with chronic hepatitis C or B, or cirrhosis (LF0719418 level 3). With regard to cigarette smoking as a possible risk factor for development of liver cancer, there are both articles supporting it and negating it; and the question still remains unresolved (LF0720714 level 3, LF0720415 level 3, LF0720316 level 3, LF0719418 level 3, LF0718219 level 3, LF0719520 level 3). Until now, two large scale studies have investigated the relationship between obesity and hepatocellular carcinoma. In the study performed in Denmark, the risk of hepatocellular carcinoma in obese patients was found to be 1.9-fold higher than in non-obese patients (LF1209321 level 3). In the prospective study conducted in the USA, the risk of death from hepatocellular carcinoma in obese patients (body mass index [BMI] >35 kg/m2) was 4.52-fold higher for men and 1.68-fold for women (LF1209422 level 2a). In Japan, a subgroup analysis in one study of patients with non-compensated cirrhosis treated with branched-chain amino acids (BCAA), in which the end-point was improvement of prognosis, revealed a high incidence of primary liver cancer in patients with a BMI of 25 or more (LF1209623 level 2a). The results of a large scale cohort study conducted in patients with diabetes mellitus in Sweden, Denmark and North America to examine the relationship between type 2 diabetes mellitus and development of liver cancer revealed that diabetes mellitus was associated with a 2–4-fold increase in the risk of development of liver cancer (LF1209724 level 2b, LF1209825 level 2b, LF1209926 level 2b). In Japan, Matsuo et al. conducted a case–control study in 225 patients in the Kyushu area and reported that diabetes mellitus was a risk factor for development of liver cancer (odds ratio: 2.5-fold), independent of the age and sex (LF1210027 level 3). Marrero et al. investigated the background characteristics of 105 hepatocellular carcinoma patients to determine the relationship between non-alcoholic steatohepatitis (NASH) and development of liver cancer, and reported that HCV showed the strongest association (51%), followed by cryptogenic cirrhosis (29%), and that half of the patients with cryptogenic cirrhosis had NASH (LF1210128 level 2b). In Japan, Hashimoto et al. followed up the clinical course of 247 patients with non-alcoholic fatty liver disease (NAFLD) and noted concurrent hepatocellular carcinoma in 10 patients with cirrhosis. The 5-year cumulative incidence of hepatocellular carcinoma was 20% in F3–4 patients showing progression to liver fibrosis (LF1210229 level 2b). COMMENTS Each of the above risk factors has been shown to independently increase the risk of development of liver cancer, and the incidence of hepatocellular carcinoma is assumed to increase with an increasing number of risk factors. While it would be ideal to score these risk factors and quantitatively evaluate them, there is, at present, no adequately examined system for such quantitation. Furthermore, it would be desirable to specify a threshold for the annual rate of carcinogenesis at which screening should be started, but that is also difficult at this point. Consequently, we select patients with usual type B or C chronic liver disease and patients with cirrhosis of various etiologies as the target population for hepatocellular carcinoma screening. REFERENCES 1 LF07209 Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet 1981; 2 (8256): 1129– 33. CrossrefCASPubMedWeb of Science®Google Scholar 2 LF07205 Yu MW, You SL, Chang AS, Lu SN, Liaw YF, Chen CJ. Association between hepatitis C virus antibodies and hepatocellular carcinoma in Taiwan. Cancer Res 1991; 51: 5621– 5. 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Additive effect modification of hepatitis B surface antigen and e antigen on the development of hepatocellular carcinoma. Br J Cancer 1996; 73: 1498– 502. CrossrefCASPubMedWeb of Science®Google Scholar 8 LF07199 Fattovich G, Giustina G, Schalm SW et al. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. Hepatology 1995; 21: 77– 82. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 9 LF07202 Liang TJ, Jeffers LJ, Reddy KR et al. Viral pathogenesis of hepatocellular carcinoma in the United States. Hepatology 1993; 18 (6): 1326– 33. Wiley Online LibraryPubMedWeb of Science®Google Scholar 10 LF03575 Tradati F, Colombo M, Mannucci PM et al. A prospective multicenter study of hepatocellular carcinoma in Italian hemophiliacs with chronic hepatitis C The Study Group of the Association of Italian Hemophilia Centers. Blood 1998; 91: 1173– 7. 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Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 15 LF07204 Tanaka K, Hirohata T, Takeshita S et al. Hepatitis B virus, cigarette smoking and alcohol consumption in the development of hepatocellular carcinoma: a case–control study in Fukuoka, Japan. Int J Cancer 1992; 51: 509– 14. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 16 LF07203 Mohamed AE, Kew MC, Groeneveld HT. Alcohol consumption as a risk factor for hepatocellular carcinoma in urban southern African blacks. Int J Cancer 1992; 51: 537– 41. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 17 LF07193 Donato F, Tagger A, Gelatti U et al. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 2002; 155: 323– 31. CrossrefCASPubMedWeb of Science®Google Scholar 18 LF07194 Chiesa R, Donato F, Tagger A et al. Etiology of hepatocellular carcinoma in Italian patients with and without cirrhosis. Cancer Epidemiol Biomarkers Prev 2000; 9: 213– 16. CASPubMedWeb of Science®Google Scholar 19 LF07182 Yu Mctong MJ, Govindarajan S, Henderson BE. Nonviral risk factors for hepatocellular carcinoma in a low-risk population, the non-Asians of Los Angeles County, California. J Natl Cancer Inst 1991; 83: 1820– 6. CrossrefPubMedWeb of Science®Google Scholar 20 LF07195 Kuper H, Tzonou A, Kaklamani E et al. Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma. Int J Cancer 2000; 85: 498– 502. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 21 LF12093 Moller H, Mellemgaard A, Lindvig K, Olsen JH. Obesity and cancer risk: a Danish record-linkage study. Eur J Cancer 1994; 30 A: 344– 50. CrossrefWeb of Science®Google Scholar 22 LF12094 Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003; 348: 1625– 38. CrossrefPubMedWeb of Science®Google Scholar 23 LF12096 Muto Y, Sato S, Watanabe A et al. Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis. Hepatol Res 2006; 35: 204– 14. CASPubMedWeb of Science®Google Scholar 24 LF12097 Adami HO, Chow WH, Nyren O et al. Excess risk of primary liver cancer in patients with diabetes mellitus. J Natl Cancer Inst 1996; 88: 1472– 7. CrossrefCASPubMedWeb of Science®Google Scholar 25 LF12098 Wideroff L, Gridley G, Mellemkjaer L et al. Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. J Natl Cancer Inst 1997; 89: 1360– 5. CrossrefCASPubMedWeb of Science®Google Scholar 26 LF12099 El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126 (2): 460– 8. CrossrefPubMedWeb of Science®Google Scholar 27 LF12100 Matsuo M. Association between diabetes mellitus and hepatocellular carcinoma: results of a hospital- and community-based case-control study. Kurume Med J 2003; 50 (3–4): 91– 8. CrossrefPubMedGoogle Scholar 28 LF12101 Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 2002; 36 (6): 1349– 54. Wiley Online LibraryPubMedWeb of Science®Google Scholar 29 LF12102 Hashimoto E, Yatsuji S, Kaneda H et al. The characteristics and natural history of Japanese patients with nonalcoholic fatty liver disease. Hepatol Res 2005; 33 (2): 72– 6. CrossrefPubMedWeb of Science®Google Scholar CQ5 Does regular screening of patients having risk factors for hepatocellular carcinoma improve the prognosis of hepatocellular carcinoma? RECOMMENDATION Regular hepatocellular carcinoma screening leads to early detection of hepatocellular carcinoma, and in turn provides an opportunity for radical treatment. It may also lead to improvement of the prognosis. (grade B) SCIENTIFIC STATEMENT One RCT reported that regular hepatocellular carcinoma surveillance might have the effect of improving the prognosis of hepatocellular carcinoma (LF106251 level 1). Among patients with HBV infection, hepatocellular carcinoma was more frequently detected in the small nodule stage, the number of patients in whom hepatectomy was feasible was significantly higher, and the survival rate was significantly higher in the group that underwent regular surveillance every 6 months by serum α-fetoprotein (AFP) measurement and ultrasonography as compared with the results in the group in whom such surveillance was not undertaken. The mortality rate also improved by 37%. Although not an RCT, a prospective study conducted only in patients with cirrhosis (LF019822 level 2a) also demonstrated that regular surveillance by ultrasonography and serum AFP measurement prolonged survival. Retrospective studies adjusted for lead-time bias (LF100863 level 2b, LF108494 level 2b, LF102745 level 2b) also reported that regular surveillance improved the survival rate; therefore, they demonstrated that regular surveillance might have a favorable effect on the prognosis. Whether early detection of hepatocellular carcinoma by surveillance might increase the number of patients receiving radical treatment was examined. Radical therapy, such as hepatectomy, local aspiration therapy and transcatheter arterial chemoembolization (TACE), was often feasible for hepatocellular carcinoma diagnosed in patients with chronic hepatitis as a result of regular surveillance by serum AFP measurement and ultrasonography, as compared with a matched group of patients with hepatocellular carcinoma who were not under surveillance and were diagnosed on the basis of the clinical symptomatology (LF021146 level 3, LF038227 level 3, LF106251 level 1, LF100863 level 2b, LF019822 level 2a). Nonetheless, another report has suggested that even if regular surveillance is performed, the opportunity for hepatectomy is not increased (LF039058 level 2a). COMMENTS In order to truly demonstrate the usefulness of hepatocellular carcinoma surveillance, it is necessary to prove that regular screening helps in the detection of the cancer at an earlier stage, that early detection increases the possibility of radical treatment and that it results in improved prognosis. In relation to hepatocellular carcinoma surveillance, there are only a few articles suggesting that these requirements can be met; thus, conclusions should be drawn carefully. There are no articles directly comparing the efficacy of surveillance between patients with chronic hepatitis and cirrhosis. There are also no articles directly comparing differences in the efficacy of surveillance between patients with chronic hepatitis B and C and taking into account risk factors such as sex, age and the level of alcohol consumption. The subjects of surveillance in each report vary slightly so that the results should be interpreted carefully taking such differences into account. When reviewing based on the annual rate of primary liver cancer, the incidence of hepatocellular carcinoma was high in studies including many patients with cirrhosis, and it was often reported that regular screening of groups at a high risk of developing hepatocellular carcinoma increased the frequency of detection of hepatocellular carcinoma as a solitary lesion or nodules, leading to increase in the changes of radical treatment. REFERENCES 1 LF10625 Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004; 130: 417– 22. CrossrefPubMedWeb of Science®Google Scholar 2 LF01982 Bolondi L, Sofia S, Siringo S et al. Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis. Gut 2001; 48: 251– 9. CrossrefCASPubMedWeb of Science®Google Scholar 3 LF10086 Trevisani F, Cantarini MC, Labate AM et al. Surveillance for hepatocellular carcinoma in elderly Italian patients with cirrhosis: effects on cancer staging and patient survival. Am J Gastroenterol 2004; 99: 1470– 6. CrossrefPubMedWeb of Science®Google Scholar 4 LF10849 Tanaka H, Nouso K, Kobashi H et al. Surveillance of hepatocellular carcinoma in patients with hepatitis C virus infection may improve patient survival. Liver Int 2006; 26: 543– 51. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 5 LF10274 Yu EW, Chie WC, Chen TH. Does screening or surveillance for primary hepatocellular carcinoma with ultrasonography improve the prognosis of patients? Cancer J 2004; 10: 317– 25. CrossrefPubMedWeb of Science®Google Scholar 6 LF02114 Yuen MF, Cheng CC, Lauder IJ, Lam SK, Ooi CG, Lai CL. Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience. Hepatology 2000; 31: 330– 5. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 7 LF03822 Tang ZY, Yu YQ, Zhou XD, Yang BH, Ma ZC, Lin ZY. Subclinical hepatocellular carcinoma: an analysis of 391 patients. J Surg Oncol Suppl 1993; 3: 55– 8. Wiley Online LibraryPubMedWeb of Science®Google Scholar 8 LF03905 Colombo M, De Franchis R, Del Ninno E et al. Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med 1991; 325: 675– 80. CrossrefCASPubMedWeb of Science®Google Scholar CQ6 How should regular screening for hepatocellular carcinoma be implemented? RECOMMENDATION Hepatocellular carcinoma screening is centered around ultrasonography combined with tumor marker measurements, with dynamic CT/MRI performed concurrently in the very high-risk group, such as patients with cirrhosis. (grade B) Regular screening at intervals of 2–6 months using tumor marker measurements and ultrasonography, in combination with dynamic CT/MRI as needed, increases the possibility of detection of hepatocellular carcinoma in the single nodule stage. (grade C1) SCIENTIFIC STATEMENT In hepatocellular carcinoma screening, the sensitivity of ultrasonography for the detection of hepatocellular carcinoma is higher as compared with that of AFP measurements (in patients with cirrhosis LF019821 level 2a, LF026872 level 2a, LF026893 level 2a; in HBV carriers LF037274 level 2a), but there was no obvious difference in specificity (LF026893 level 2a, LF037274 level 2a). In addition, it has been reported that there is no significant difference in the detection sensitivity between ultrasonography alone and ultrasonography plus AFP measurements for hepatocellular carcinoma surveillance (LF037274 level 2a). In contrast, according to one report, use of ultrasonography and AFP measurements in combination as screening procedures increased the sensitivity of detection of hepatocellular carcinoma as compared with the use of either test alone in cirrhosis patients (LF026893 level 2a). The sensitivity and specificity of screening ultrasonographic diagnosis of hepatocellular carcinoma in patients with chronic hepatitis or cirrhosis are reportedly 78–90% and 93–93.8%, respectively (LF026893 level 2a, LF037274 level 2a, LF030695 level 4). When hepatocellular carcinoma is not detected by ultrasonographic screening, it is often present in blind areas such as under the diaphragm or in the presence of a rough background liver (LJ034716 level 1). The detection capability of ultrasonography has frequently been reported to be inferior to that of MRI or CT (LF061987 level 1, LF020018 level 1, LF008079 level 1). In a recent study of livers from liver transplant patients, the sensitivity of ultrasonography for the detection of hepatocellular carcinoma nodules was as low as 20.5% (LF0186710 level 2b), and especially low for nodules 2 cm or less in diameter (LF0040611 level 3, LF0186710 level 2b). In contrast, according to one study in patients with nodules 2 cm or less in diameter, the detection capability of ultrasonography for such lesions was superior to that of MRI or CT (LF0223112 level 1). There are no report of any RCT that have examined differences in the detection rate of hepatocellular carcinoma according to differences in the screening interval, such as 3 months, 6 months and 1 year. In most cases of hepatocellular carcinoma detected by screening of chronic hepatitis and cirrhosis patients by a combination of regular AFP measurements and ultrasonography, the tumor was single (LF019821 level 2a, LF026872 level 2a, LF0246213 level 2a) and small in size (LF0246213 level 2a, LF0211414 level 3, LF0382215 level 3) as compared with the findings in cases of hepatocellular carcinoma detected based on the manifestation of clinical symptoms. In one study of patients with cirrhosis who were screened by AFP measurements every 2 months and ultrasonography every 3 months, 65% of the detected hepatocellular carcinomas were 2 cm or less in diameter (LF0294516 level 2a). In another study in which patients with chronic liver disease were screened by AFP measurements and ultrasonography every 4 and 6 months, 93.3% (LF0187117 level 4) and 80.4% (LF019821 level 2a) of the detected cases were single tumors, respectively. In one study in which the patients were screened by AFP measurements and ultrasonography every 4 months, the mean diameter of tumors at the time of detection was 18.3 mm (LF0187117 level 4). In some studies in which cirrhosis patients were screened by AFP measurements and ultrasonography every 6 months, 75–86.7% of the detected hepatocellular carcinomas were single tumors (LF019821 level 2a, LF026872 level 2a, LF0246213 level 2a); according to another study, the tumor size at the time of detection was 3 cm or less in all the patients (LF0390518 level 2a). In a population that was screened by AFP measurements and ultrasonography every 3–12 months, 58% of the detected hepatocellular carcinomas were single tumors (LF0390518 level 2a). COMMENTS Hepatocellular carcinoma surveillance by combined ultrasonography and AFP measurements has not been clearly shown to be superior to surveillance using either test alone. Because at least the sensitivity was improved by the use of both methods in combination, at present, the two are generally used together for hepatocellular carcinoma screening in Japan. However, whether such screening has resulted in any enhancement of the diagnostic capability remains unclear. It is difficult to set an appropriate interval for regular screening based on the accumulated evidence until date. Nonetheless, if regular screening by combined AFP measurements and ultrasonography is performed every 2–6 months, the likelihood of detection of hepatocellular carcinoma in the single and small nodule stage is high. This interval may also be appropriate from the perspective of the doubling time of hepatocellular carcinoma. As an imaging modality, ultrasonography has blind areas and inadequate capability to detect tumors, particularly those that are 2 cm or less in diameter, in the presence of liver cirrhosis, which results in a rough echo pattern of the background liver. Therefore, in hepatocellular carcinoma screening, the detection capability may be expected to increase if other imaging tests are performed in addition to ultrasonography, such as CT and MRI. However, there are few studies on hepato