The steatohepatitic variant of hepatocellular carcinoma and its association with underlying steatohepatitis

Summary

Steatohepatitis and metabolic syndrome are increasingly recognized as important risk factors for development of hepatocellular carcinoma. We have recently described a histologic subtype of hepatocellular carcinoma termed steatohepatitic hepatocellular carcinoma, which shows features resembling steatohepatitis in the nonneoplastic liver. The present study is undertaken to assess the association between the steatohepatitic hepatocellular carcinoma variant and underlying steatohepatitis and features of metabolic syndrome. We examined all hepatocellular carcinomas diagnosed on resections and explant specimens over a 3.5-year period at our institution. Tumors were classified as either conventional hepatocellular carcinoma or steatohepatitic hepatocellular carcinoma variant based on their predominant histopathologic pattern. The underlying chronic liver disease in each case was determined. The steatohepatitic hepatocellular carcinoma variant represented 13.5% (16/118) of cases. All but one case of steatohepatitic hepatocellular carcinoma occurred in patients with underlying steatohepatitis. Steatohepatitic hepatocellular carcinoma was diagnosed in 35.7% of patients with either nonalcoholic steatohepatitis or alcoholic liver disease compared with 1.3% of patient with other chronic liver diseases (P < .0001). The steatohepatitic hepatocellular carcinoma group had a significantly higher number of metabolic syndrome risk factors (2.44 versus 1.48, P = .01) and a higher percentage of patients with at least 3 metabolic syndrome components (50% versus 22.5%, P = .02). Immunohistochemically, there were diffuse loss of cytoplasmic CK8/18 and increased numbers of activated hepatic stellate cells within steatohepatitic hepatocellular carcinoma, in a pattern identical to that seen in steatohepatitis in nonneoplastic liver. Hepatocellular carcinomas showing a “steatohepatitic” histologic phenotype are strongly associated with underlying steatohepatitis and metabolic syndrome. This association further supports a possible role of steatohepatitis in human hepatocarcinogenesis.

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third most common cause of cancer-related death [1]. In the United States, the incidence of HCC has increased by 80% in the last 2 decades [2]. A similar trend has been observed in many developed countries including Canada, Japan, Australia, and Western European nations [3], [4]. Although conditions such as chronic viral hepatitis B and C, alcoholic liver disease (ALD), and hemochromatosis, among others, are generally regarded as established risk factors for HCC, there is now compelling evidence to suggest that nonalcoholic fatty liver disease (NAFLD) may represent the underlying etiology of HCC in a significant number of cases [5], [6], sometimes in the absence of cirrhosis [7], [8]. Recent studies also indicate that obesity [9], [10] and diabetes [11], [12] may be independent risk factors for HCC. With the frequency of chronic hepatitis C (HCV)–related transplants having reached its peak in 2002 and in view of the rapidly growing epidemics of obesity and diabetes, NAFLD is projected to become the most common indication for liver transplantation in the United States in the next decade [13], [14], [15]; and an increasing number of HCCs arising in this setting is likely to be seen.

Different histologic variants and growth patterns of HCC have been described [16]. However, with the exception of fibrolamellar HCC, which tends to occur in young, noncirrhotic patients [17], none of the patterns described to date are thought to bear clinical significance or correlation with specific underlying liver diseases. Our group has previously described the histopathologic features of a novel histologic variant of HCC in patients undergoing liver transplantation for HCV referred to as steatohepatitic HCC (SH-HCC). This variant shows histopathologic features reminiscent of steatohepatitis in nonneoplastic liver, namely, inflammation, hepatocyte ballooning, Mallory-Denk bodies (MDBs), and pericellular fibrosis [18]. This variant was first recognized by our group in a selected population of patients with HCV-related HCCs. The authors have since noticed a significant proportion of HCC cases showing a “steatohepatitic” morphology arising in patients in whom steatohepatitis (both alcoholic and nonalcoholic) was the only underlying liver disease. In view of the rapidly growing epidemics of metabolic syndrome and steatohepatitis, it became crucial to determine the frequency of this variant among all HCCs and to assess whether the SH-HCC variant is associated with underlying steatohepatitis in a comprehensive group of patients diagnosed with HCC in the setting of various chronic liver diseases.