AJM Theme Issue: Gastroenterology
Review
Hepatocellular Cancer: A Guide for the Internist

https://doi.org/10.1016/j.amjmed.2006.11.020Get rights and content

Abstract

Hepatocellular cancer is the third leading cause of cancer-related deaths worldwide. Its incidence has increased dramatically in the United States because of the spread of hepatitis C virus infection and is expected to increase for the next 2 decades. Hepatitis B virus, hepatitis C virus, and chronic heavy alcohol use leading to cirrhosis of the liver remain the most important causes. The diagnosis of hepatocellular cancer rests on a combination of radiologic, serologic, and histopathologic criteria. Liver transplantation is the only definitive treatment. Resection of the tumor and other percutaneous therapies are more commonly used in practice, because most hepatocellular cancers are detected at an advanced stage. Patients who are at high risk for the development of hepatocellular cancer should be screened with an ultrasound of the liver every 6 months. The prognosis is dependent on both the underlying liver function and the stage at which the tumor is diagnosed. The aim of this review is to familiarize internists in screening, diagnosis, and referral of patients with hepatocellular cancer in an appropriate and timely fashion.

Section snippets

Epidemiology

Hepatocellular cancer is a major health problem; more than half a million cases are reported yearly worldwide. The geographic areas most affected are located in Southeast Asia and sub-Saharan Africa. More recently, an increasing number of cases have been identified in Western countries. A large, retrospective cohort study confirmed an almost 2-fold increase in the incidence of hepatocellular cancer from 1975 to 1998 in the United States.2, 3 This increase is primarily related to the spread of

Cause

The major clinical risk factor for the development of hepatocellular cancer is cirrhosis of the liver. Chronic infections with hepatitis B virus (HBV) and HCV and chronic heavy alcohol use are the most important risk factors for the development of cirrhosis. HBV accounts for the majority of hepatocellular cancer in China and Africa, where most of the infection is acquired early in life either from mother to the offspring or by horizontal transmission.8, 9 In contrast, HCV accounts for most of

Clinical Features

The typical clinical manifestations of hepatocellular cancer are right upper quadrant abdominal pain, early satiety, and weight loss. However, more and more hepatocellular cancers are now detected at an asymptomatic stage because of the growing awareness of these tumors in patients with chronic liver disease and cirrhosis.19 Other clinical presentations, such as spontaneous rupture of the tumor into the peritoneal cavity, obstructive jaundice, and bony pain from metastasis, are extremely

Diagnosis

A consensus statement from the European Association for the Study of Liver Diseases (EASL) has been formulated to help clinicians standardize diagnostic approaches20 (Table 2).

Screening

Although there is no definite evidence that screening in hepatocellular cancer improves survival, many physicians screen patients in high-risk groups with either serum alpha-fetoprotein or ultrasound of the liver or both. Two recent randomized controlled trials completed in China demonstrated a significant reduction in hepatocellular cancer-related mortality in patients who underwent screening.37, 38 Ultrasound of the liver is the preferred screening test because it has a sensitivity of 84% and

Natural History and Prognosis

Prospective studies have shown that most hepatocellular cancers develop through a progressive pathway from premalignant nodular lesions to cancerous lesions in the cirrhotic liver.43 Progression takes an average of approximately 2 to 4 decades from the initial time of infection with HBV or HCV to the development of cirrhosis. Thereafter, the annual risk of hepatocellular cancer is 2% to 3% for HBV, 1% to 7% for HCV, and 1% for alcohol-induced cirrhosis.10, 44 Hepatocellular cancer can develop

Management

The definitive treatment of hepatocellular cancer is liver transplantation; this cures both the cancer and the underlying cancer-prone cirrhotic liver (Figure 2).

Future Trends

Proteomics has led to the discovery of new molecular markers, such as des-gamma carboxyprothrombin and human hepatocyte growth factor, for screening hepatocellular cancer, and these are being validated for clinical use. Antiangiogenesis agents such as vascular endothelial growth factor antibodies and thalidomide, nonspecific inhibitors of carcinogenesis such as Sandostatin and arsenic, and better means of delivering radiation such as yttrium microspheres are all being actively investigated for

Conclusion

The incidence of hepatocellular cancer is increasing in the Western world, including the United States. Although HBV, HCV, and alcohol use constitute the most important risk factors for the development of hepatocellular cancer, diabetes and obesity may contribute to increased carcinogenicity. Primary care physicians taking care of patients with chronic viral hepatitis and cirrhosis will need to have a heightened awareness of hepatocellular cancer, because the translation of bench research into

Acknowledgments

We are indebted to Drs Richard Goodgame, Hashem El-Serag, and Prashant Kapoor for their critical review of this article.

References (73)

  • M.F. Yuen et al.

    Serological markers of liver cancer

    Best Pract Res Clin Gastroenterol

    (2005)
  • M.S. Peterson et al.

    Radiologic diagnosis of hepatocellular carcinoma

    Clin Liver Dis

    (2001)
  • M. Omata et al.

    Prevention of hepatocellular carcinoma and its recurrence in chronic hepatitis C patients by interferon therapy

    Clin Gastroenterol Hepatol

    (2005)
  • J. Belghiti et al.

    Seven hundred forty seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection

    J Am Coll Surg

    (2000)
  • M.P. Bralet et al.

    Hepatocellular carcinoma occurring in nonfibrotic liver: epidemiologic and histopathologic analysis of 80 French cases

    Hepatology

    (2000)
  • H. Imamura et al.

    Risk factors contributing to early and late intrahepatic recurrence of hepatocellular carcinoma after hepatectomy

    J Hepatol

    (2003)
  • W.Y. Lau et al.

    Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomized trial

    Lancet

    (1999)
  • T. Takayama et al.

    Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomized trial

    Lancet.

    (2000)
  • E. Regalia et al.

    Liver transplantation for small hepatocellular carcinoma in cirrhosis: analysis of our experience

    Transplant Proc

    (2001)
  • I.W. Graziadei et al.

    Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome

    Liver Transpl

    (2003)
  • S.M. Lin et al.

    Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or equal to 4 cm

    Gastroenterology.

    (2004)
  • J.M. Llovet et al.

    Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival

    Hepatology

    (2003)
  • A. Burroughs et al.

    Systemic treatment and liver transplantation for hepatocellular carcinoma: two ends of the therapeutic spectrum

    Lancet Oncol

    (2004)
  • F.Y. Yao et al.

    Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival

    Hepatology

    (2001)
  • D.M. Parkin et al.

    Estimating the world cancer burden: Globocan 2000

    Int J Cancer

    (2001)
  • H.B. El-Serag et al.

    Rising incidence of hepatocellular cancer in the United States

    N Engl J Med

    (1999)
  • H.B. El-Serag et al.

    The continuing increase in the incidence of Hepatocellular carcinoma in the United States: an update

    Ann Intern Med

    (2003)
  • Y. Tanaka et al.

    A comparison of the molecular clock of hepatitis C virus in the United States and Japan predicts that hepatocellular carcinoma incidence will increase in the next two decades

    Proc Natl Acad Sci U S A

    (2002)
  • American Cancer Society. Cancer Facts and Figures 2007. Available at: http://www.cancer.org/downloads. Accessed January...
  • B.I. Carr et al.

    Cancers of the Liver

    Cancer: Principles and Practice of Oncology

    (2004)
  • H. Tsukuma et al.

    Risk factors for hepatocellular carcinoma among patients with chronic liver disease

    N Engl J Med

    (1993)
  • F.S. Yeh et al.

    Hepatitis B virus, aflatoxins, and hepatocellular carcinoma in southern Guangxi, China

    Cancer Res

    (1989)
  • F. Donato et al.

    A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma

    Int J Cancer

    (1998)
  • A.N. Elzouki et al.

    Risk of hepatobiliary disease in adults with severe alpha 1-antitrypsin deficiency (PiZZ): is chronic viral hepatitis B or C an additional risk factor for cirrhosis and hepatocellular carcinoma?

    Eur J Gastroenterol Hepatol

    (1996)
  • H. Kuper et al.

    Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma

    Int J Cancer.

    (2000)
  • B. Bressac et al.

    Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa

    Nature

    (1991)
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