Detection and Characterization of Hepatocellular Carcinoma by Imaging

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1 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, Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan In cirrhotic livers, several types of hepatocellular nodules are found during the diagnosis of hepatocellular carcinoma (HCC). To characterize the nodules is imperative for the optimal management of cirrhotic patients. However, the definitive distinction between early stage, well-differentiated HCC and borderline lesions is still difficult because histologic differences among these nodules are sequential. Therefore, it is important to appreciate the changes on imaging with the progression from benign precancerous nodule to overt HCC and to predict the prognosis of the nodules on the basis of these imaging findings. Epidemiology and Detection of Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Around 560,000 new cases were seen in ,2 It accounts for around 5.6% of all cancers worldwide. The incidence of HCC is different among various geographic areas. In Southeast Asia and southern Africa, the incidence is more than 20 per 100,000 per year. On the other hand, it is less than 5 per 100,000 per year in the United States, United Kingdom, and other North European countries. The geographic difference in the incidence of HCC is due to the differences of etiology of HCC. There are various kinds of etiologic factors in HCC. Among them, persistent infection of hepatitis B virus (HBV), persistent infection of hepatitis C virus (HCV), and alcoholic cirrhosis are most common. 2 The main cause of HCC in Southeast Asia is HBV infection. However, in Japan, HCV infection is the main cause, as in the United States or European countries. In Japan, around 32,000 deaths per year, around 30 per 100,000 per year, are caused by HCC, and HCC is the third most common cancer in men and the fifth most common in women. 3 Around 90% of HCC are associated with chronic liver disease caused by HCV or HBV infection. 4 It is wellknown that there is a strong correlation between the degree of hepatic fibrosis and the incidence of HCC in an HCV-infected liver. In the absence of fibrosis (F0) stage, HCC is extremely rare. The expected annual incidence of HCC is 0.5% in F1, 1% 2% in F2, 4% 5% in F3, and 6% 7% in F4. 5,6 In clinical practice, the platelet count is very useful to predict the degree of fibrosis. In F3 stage, the platelet count is around 100, , /L, and in F4, it is less than 100, /L. 4 Therefore, patients with hepatitis C or B related cirrhosis or chronic hepatitis with F3 grade of portal tract fibrosis with platelet count less than 140,000 are the super-high risk group. Patients with hepatitis C or B related chronic hepatitis with less than F2 stage and other types of cirrhosis are the relatively high-risk group. Therefore, it has become possible to detect small, earlystage HCC by periodic screening in these groups of high-risk patients. For the screening of HCC, serum tumor marker measurement and ultrasound are carried out every 3 months and dynamic computed tomography (CT) every 6 12 months (Figure 1). If some abnormalities are found, magnetic resonance imaging (MRI) and/or angiography including CT during arterial portography (CTAP) and CT during hepatic arteriography (CTHA) are performed. When the imaging diagnosis is difficult, biopsy under ultrasound guidance is carried out. According to the 15th nationwide survey by Liver Cancer Study Group of Japan, around 75% of HCC cases newly diagnosed during were less than 5 cm in diameter, with the majority less than 3 cm in diameter 7 (Figure 2). HCC detected by periodic screening in high-risk patients are usually less than 2 5 cm. However, multicentric HCC and/or borderline lesions are also Abbreviations used in this paper: CT, computed tomography; CTAP, computed tomography during arterial portography; CTHA, computed tomography during hepatic arteriography; DN, dysplastic nodule; HCC, hepatocellular carcinoma; MRI, magnetic resonance imaging by the American Gastroenterological Association /05/$30.00 PII: /S (05)00707-X

Characterization of Hepatic Nodules and Multi-step Carcinogenesis Hepatocellular nodules associated with cirrhosis are divided histologically into 6 categories according to the classification

2 October Supplement 2005 DETECTION AND CHARACTERIZATION OF HCC BY IMAGING S137 Figure 1. Screening protocol for HCC in Japan. AFP, alpha-fetoprotein; PIVKA, protein induced by vitamin K absence or antagonism. found in around 60% of patients with small HCC, especially in patients with hepatitis C related cirrhosis. Characterization of Hepatic Nodules and Multi-step Carcinogenesis Hepatocellular nodules associated with cirrhosis are divided histologically into 6 categories according to the classification proposed by the Liver Cancer Figure 3. Early HCC (highly well-differentiated HCC) with fatty metamorphosis. (A) Hematoxylin-eosin stain; original magnification 1 (arrows indicate the lesion). (B) Hematoxylin-eosin stain; original magnification 200. Figure 2. A minute, moderately differentiated HCC detected by periodic CT examination. (A) Arterial dominant phase of dynamic CT revealed a minute, enhanced nodule (center, arrow). Left, precontrast CT; right, postcontrast CT. (B) Resected specimen demonstrated a moderately differentiated HCC around 1 cm in diameter (arrow). Study Group of Japan. 8 Large regenerative nodule is a distinct nodular lesion of around cm in diameter grossly, but histologically not different from the surrounding regenerative nodules. Adenomatous hyperplasia is a distinct and expansive nodular lesion that is clearly larger (more than 8 mm in diameter) than surrounding regenerative nodules. Microscopically, it is a nodule composed of nonmalignant hepatocytes containing complete portal tracts having a portal vein, hepatic artery, and bile duct. The cell density is moderately increased compared with the surrounding regenerative nodules, but structural atypia is not seen. Because of the slight decrease of cytoplasm, the nuclear/cytoplasmic ratio is slightly increased. Atypical adenomatous hyperplasia consists of focal areas with mild structural atypia or markedly increased cell density seen in the nodule. Early HCC is defined as cellularity of the lesion more than double that of the surrounding liver, showing acinar or cord structural atypia at some areas and smaller hepatocytes (Figure 3). In well-differentiated HCC, the lesion has an irregular, thin trabecular pattern arranged in 2 or 3 layers and/or pseudoglandular pattern. The degree of

hypodense nodule on CTAP (left, arrow), indicating partially absent intranodular portal supply (group C).

3 S138 OSAMU MATSUI CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 10 Figure 4. High-grade DN with malignant subfocus (one type of early HCC). (A) A tiny hypervascular focus in entirely isodense nodule is shown on CTHA (right, arrow), indicating partially increased arterial supply (group III), and definitely hypodense focus in slightly hypodense nodule on CTAP (left, arrow), indicating partially absent intranodular portal supply (group C). (B) Surgical resection revealed highgrade DN with a malignant subfocus (HCC, well-differentiated HCC; HDN, high-grade DN). cell atypia is almost the same as Edmondson-Steiner grade I. In moderately or poorly differentiated HCC, the lesion occasionally shows a trabecular pattern arranged in more than several layers, corresponding to the category of Edmondson-Steiner grade II or III of cell atypia (usually called classic HCC in Japan). According to the classification proposed by the International Working Party of the World Congress of Gastroenterology in 1994, 9 these nodules are divided into 4 categories, namely low-grade dysplastic nodule (DN), high-grade DN, well-differentiated HCC, and moderately or poorly differentiated HCC. Low-grade DN is considered to be consistent with adenomatous hyperplasia, and high-grade DN is considered to be consistent with atypical adenomatous hyperplasia and the majority of early HCC in the classification proposed by the Liver Cancer Study Group of Japan. In this article, the latter classification is used, and early HCC is described as highly well-differentiated HCC. It is of interest that cancerous foci of well-differentiated HCC are occasionally encountered within a high-grade DN nodule (nodule in nodule lesions) (Figure 4). However, histopathologic definition, identification, and significance of low-grade DN remain unclear. These nodules can be included in the group of regenerative nodules with unusual histologic changes. 10 Hepatocellular nodules become larger in accordance with the grade of malignancy of the nodules. In our experience, the average size of low-grade DN was around 1 cm in diameter, high-grade DN 1.3 cm, well-differentiated HCC 1.6 cm, and classic HCC 2.2 cm (unpublished data). However, there was overlap with a wide range of diameters among these nodules. To characterize these nodules is important for the management of patients with cirrhosis. However, because of histologic continuity among these nodules and internal histologic heterogeneity in these nodules, the precise differential diagnosis is often difficult, even in histology. Therefore, understanding the sequential changes of the intranodular blood supply in accordance with the progression of benign hepatocellular nodule to overt HCC by using imaging findings is necessary for the characterization of these nodules. For this purpose, evaluation of the intranodular blood supply by using imaging is useful. According to our analysis, there is a strong correlation between intranodular blood supply and human hepatocarcinogenesis. For the analysis of intranodular portal supply, CTAP is most effective, and for the evaluation of intranodular arterial supply, CTHA is most sensitive. CTAP findings seen in these nodules were divided into 4 groups. In group A, the nodule was not identified, indicating almost the same intranodular portal supply relative to the surrounding liver (Figure 5). In group B, the nodule was visualized as a slightly hypodense area, indicating decreased intranodular portal supply (Figure 6). In group C, a part of the nodule showed definite hypodensity, indicating partial absence of intranodular portal supply (Figure 4). In group D, the nodule was seen as a definitely hypodense area, indicating absence of intranodular portal supply (Figure 7). There Figure 5. High-grade DN. CTHA (right, arrow) shows hypodensity relative to the surrounding liver, indicating decreased intranodular arterial supply (group II). CTAP shows isodensity, indicating almost the same intranodular portal supply (left, arrow) (group A).

October Supplement 2005 DETECTION AND CHARACTERIZATION OF HCC BY IMAGING S139 Figure 6. Early HCC (highly well-differentiated HCC).

CTAP shows slight hypodensity, indicating almost the same intranodular portal supply (right, arrow) (group B).

CTHA findings were also divided into 4 groups. In group I, the nodule was not identified, indicating almost the same intranodular arterial supply relative to the surrounding liver (Figure 6).

4 October Supplement 2005 DETECTION AND CHARACTERIZATION OF HCC BY IMAGING S139 Figure 6. Early HCC (highly well-differentiated HCC). CTHA (right, arrow) shows isodensity relative to the surrounding liver, indicating almost the same intranodular arterial supply (group I). CTAP shows slight hypodensity, indicating almost the same intranodular portal supply (right, arrow) (group B). were statistically significant correlations between lowgrade DN and group A, high-grade DN and group B, well-differentiated HCC and group C, and classic HCC and group D. CTHA findings were also divided into 4 groups. In group I, the nodule was not identified, indicating almost the same intranodular arterial supply relative to the surrounding liver (Figure 6). In group II, the nodule was shown as a hypodense area, indicating decreased arterial blood supply (Figure 5). In group III, a partial hyperdense area was seen in a nodule, indicating partial increase of arterial supply (Figure 4). In group IV, the entire nodule demonstrated hyperdensity, indicating diffusely increased intranodular arterial supply (Figure 7). There was significant correlation between classic HCC and group IV. There was a strong tendency for low-grade DN to show group I, high-grade DN to show group II, and well-differentiated HCC to show group III. However, early (highly well-differentiated) HCC showed types I, II, and III with almost the same frequency. According to our histologic study, 13 there were 3 feeding vessels in these nodules, namely normal portal vein and hepatic artery included in portal tracts and abnormal artery induced by the tumor. In accordance with the elevation of the grade of malignancy of the Figure 7. Moderately differentiated HCC (classic HCC). CTHA (right, arrow) shows definite hyperdensity, indicating markedly increased intranodular arterial supply (group IV). CTAP shows definite hypo density, indicating absent intranodular portal supply (left, arrow) (group D). Figure 8. Diagram of the stepwise changes of the intranodular blood supply during human hepatocarcinogenesis. LRN, large regenerative nodule; LDN, low-grade DN; HDN, high-grade DN; e-hcc, early HCC; wd-hcc, well-differentiated HCC. nodules, the portal tracts that included normal portal vein and hepatic artery were decreased. On the other hand, abnormal artery gradually increased. Figure 8 shows the concept obtained by these imaging and histologic studies. The portal tracts including portal vein and hepatic artery were decreased in accordance with increasing grade of malignancy and virtually absent in classic HCC. In contrast, abnormal arteries caused by tumor angiogenesis developed in high-grade DN during the course of hepatocarcinogenesis and were markedly increased in number in moderately differentiated HCC. We also demonstrated that there is a strong correlation between intranodular blood supply and the prognosis of the nodules. 14 The nodules showing almost the same intranodular portal and arterial supply did not transform to hypervascular classic HCC within 3 years. On the other hand, around 30% of the nodules showing decreased portal or arterial supply changed to hypervascular HCC within 3 years, and almost all of the nodules showing partially absent intranodular portal or partially increased arterial supply transformed to hypervascular HCC within 2 years. These findings obtained by CTAP and CTHA are very important clinically, and they should therefore be applied to noninvasive imaging diagnosis such as Doppler ultrasound, dynamic CT, and dynamic MRI. Clinically, detection of a hypervascular spot in a hypovascular nodule is important to predict the prognosis of the nodule, because this kind of nodule always progresses to entirely hypervascular classic HCC (Figure 9). Conclusion In cirrhotic livers, various types of hepatocellular nodules are found during the diagnosis of HCCs, and to characterize them is imperative for the optimal management of patients with cirrhosis. However, the definitive distinction between early-stage, well-differentiated HCC and borderline lesions is still difficult even with histol-

5 S140 OSAMU MATSUI CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 10 Figure 9. Dynamic CT in high-grade DN with a malignant subfocus. On portal phase of dynamic CT, the entire tumor is shown as hypodense nodule (right, arrow). On arterial dominant phase, a tiny enhanced focus is demonstrated in the nodule (middle, arrow). On precontrast CT, this nodule is seen as a faintly hypodense nodule (left, arrow). (The same case as shown in Figure 4.) ogy, because histologic differences among these nodules are sequential. Therefore, knowledge of the sequential changes of imaging findings in accordance with the progression from benign precancerous nodule to overt HCC and prediction of the prognosis of nodules on the basis of these imaging findings are important clinically. References 1. Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer burden: GLOBOCAN Int J Cancer 2001;94: Llovet J, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362: Higuchi M, Tanaka E, Kiyosawa K. Epidemiology and clinical aspects on hepatitis C. Jpn J Infect Dis 2002;55: Miyazawa K, Moriyama M, Mikuni M, et al. Analysis of background factors and evaluation of a population at high risk of hepatocellular carcinoma. Intervirology 2003;46: Ikeda K, Saitoh S, Suzuki Y, et al. Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: a prospective observation of 2215 patients. J Hepatol 1998;28: Yoshida H, Shiratori Y, Moriyama M, et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan IHIT Study Group Inhibition of Hepatocarcinogenesis by Interferon Therapy. Ann Intern Med 1999;131: Ikai I, Itai Y, Okita K, et al. Report of the 15th follow-up survey of primary liver cancer. Hepatol Res 2004;28: Liver Cancer Study Group of Japan. The general rules for the clinical and pathological study of primary liver cancer (in Japanese). 4th ed. Tokyo: Kanahara, 2001: International Working Party. Terminology of nodular hepatocellular lesions. Hepatology 1995;22: Nakanuma Y, Hirata K, Terasaki S, et al. Analytical histopathological diagnosis of small hepatocellular nodules in chronic liver diseases. Histol Histopathol 1998;13: Matsui O, Kadoya M, Kameyama T, et al. Benign and malignant nodules in cirrhotic livers: distinction based on blood supply. Radiology 1991;178: Hayashi M, Matsui O, Ueda K, et al. Correlation between the blood supply and grade of malignancy of hepatocellular nodules associated with liver cirrhosis: evaluation by CT during intraarterial injection of contrast medium. AJR 1999;172: Ueda K, Terada T, Nakanuma Y, et al. Vascular supply in adenomatous hyperplasia of the liver and hepatocellular carcinoma: a morphometric study. Hum Pathol 1992;23: Hayashi M, Matsui O, Ueda K, et al. Progression to hypervascular hepatocellular carcinoma: correlation with intranodular blood supply evaluated with CT during intraarterial injection of contrast material. Radiology 2002;225: Address requests for reprints to: Osamu Matsui, MD, Kanazawa University, Postgraduate School of Medicine, Department of Radiology, 13-1 Takara-machi, Kanazawa , Japan. matsuio@med.kanazawa-u.ac.jp; fax:

Hepatocelluar nodules in liver cirrhosis: hemodynamic evaluation (angiographyassisted CT) with special reference to multi-step hepatocarcinogenesis

Hepatocelluar nodules in liver cirrhosis: hemodynamic evaluation (angiographyassisted CT) with special reference to multi-step hepatocarcinogenesis Abdominal Imaging ª The Author(s) 2011. This article is published with open access at Springerlink.com Published online: 26 January 2011 Abdom Imaging (2011) 36:264 272 DOI: 10.1007/s00261-011-9685-1 INVITED