General Information

Note: Estimated new cases and deaths from liver and intrahepatic bile duct cancer in the United States in 2005:[1]

• New cases: 17,550.
• Deaths: 15,420.

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Hepatocellular carcinoma is a tumor that is relatively uncommon in the United States, although its incidence is rising, principally in relation to the spread of hepatitis C infection.[2] It is the most common cancer in some parts of the world, with more than one million new cases diagnosed each year. Hepatocellular carcinoma is potentially curable by surgical resection, but surgery is the treatment of choice for only the small fraction of patients with localized disease.[3] Prognosis depends on the degree of local tumor replacement and the extent of liver function impairment. Therapy other than surgical resection is best administered as part of a clinical trial. Such trials evaluate the efficacy of systemic or infusional chemotherapy, hepatic artery ligation or embolization, percutaneous ethanol injection, radiofrequency ablation, cryotherapy, and radiolabeled antibodies, often in conjunction with surgical resection and/or radiation therapy. In some studies of these approaches, long remissions have been reported.[3] A few patients may be candidates for liver transplantation, but the limited availability of livers for transplantation restricts the use of this approach.[4] Hepatocellular carcinoma can coexist with bile duct cancer (cholangiocarcinoma).[5]

Risk factors

Hepatocellular carcinoma is associated with cirrhosis in 50% to 80% of patients; 5% of cirrhotic patients eventually develop hepatocellular cancer, which is often multifocal.

Hepatitis B infection [3,6] and hepatitis C infection [7] appear to be the most significant causes of hepatocellular carcinoma worldwide, particularly in patients with continuing antigenemia and in those who have chronic active hepatitis. A series found that male patients older than 50 years who have both hepatitis B and hepatitis C infection may be at particularly high risk for hepatocellular cancer.[8] [Level of evidence: 3iiiDiii] There is evidence that patients with both hepatitis B and hepatitis C infection who consume more than 80 grams of alcohol per day have an increased risk of developing cancer (odds ratio [OR] = 7.3) when compared to patients who abstain from alcohol.[9] Additionally, having a first-degree relative with hepatitis B plus hepatocellular carcinoma is associated with an increased risk (OR = 2.41) for family members who are hepatitis B carriers.[10]

Aflatoxin has also been implicated as a factor in the etiology of primary liver cancer in parts of the world where this mycotoxin occurs in high levels in ingested food.[6,11] Workers who were exposed to vinyl chloride before controls on vinyl chloride dust were instituted developed sarcomas in the liver, most commonly angiosarcomas. Other sarcomas of smooth muscular and vascular origin are also found.

The primary symptoms of hepatocellular carcinoma are those of a hepatic mass. Among patients with underlying cirrhotic disease, a progressive increase in alpha-fetoprotein (AFP) and/or in alkaline phosphatase or a rapid deterioration of hepatic function may be the only clue to the presence of the neoplasm. Infrequently, patients with this disease have polycythemia, hypoglycemia, hypercalcemia, or dysfibrinogenemia.

Prognostic factors

The biologic marker AFP is useful for the diagnosis of this neoplasm. By a radioimmunoassay technique, 50% to 70% of patients in the United States who have hepatocellular carcinoma have elevated levels of AFP. However, patients with other malignancies (germ cell carcinoma and, rarely, pancreatic and gastric carcinoma) also demonstrate elevated serum levels of this protein. AFP levels have been shown to be prognostically important, with the median survival of AFP-negative patients significantly longer than that of AFP-positive patients.[12,13] Other prognostic variables include performance status, liver functions,[14] and the presence or absence of cirrhosis and its severity in relation to the Child-Pugh classification.[15]

Patients scheduled for possible resection require preoperative assessment with angiography in conjunction with helical computed tomographic (CT) scan or magnetic resonance imaging (MRI) with magnetic resonance angiography; these scans have obviated the need for angiography in most patients. Information on the arterial anatomy is helpful for the operating surgeon and may eliminate some patients from consideration for resection. The presence of tumor thrombi in the hepatic veins, the inferior vena cava, or the portal vein can significantly alter treatment approaches. Dynamic CT and MRI scans can document the relationship of the tumor to the hepatic and portal veins (and, on occasion, involvement of these structures), delineating tumors for which the chances for surgical cure are remote.[16] Laparoscopic evaluation may detect metastatic disease, bilobar disease, or inadequate liver remnant, and therefore obviate the need for open surgical exploration.[17]

References

1. American Cancer Society.: Cancer Facts and Figures 2005. Atlanta, Ga: American Cancer Society, 2005. Also available online. Last accessed May 20, 2005. 
2. El-Serag HB, Mason AC: Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 340 (10): 745-50, 1999.  [PUBMED Abstract]
3. Mor E, Kaspa RT, Sheiner P, et al.: Treatment of hepatocellular carcinoma associated with cirrhosis in the era of liver transplantation. Ann Intern Med 129 (8): 643-53, 1998.  [PUBMED Abstract]
4. Klintmalm GB: Liver transplantation for hepatocellular carcinoma: a registry report of the impact of tumor characteristics on outcome. Ann Surg 228 (4): 479-90, 1998.  [PUBMED Abstract]
5. Jarnagin WR, Weber S, Tickoo SK, et al.: Combined hepatocellular and cholangiocarcinoma: demographic, clinical, and prognostic factors. Cancer 94 (7): 2040-6, 2002.  [PUBMED Abstract]
6. Blumberg BS, Larouzé B, London WT, et al.: The relation of infection with the hepatitis B agent to primary hepatic carcinoma. Am J Pathol 81 (3): 669-82, 1975.  [PUBMED Abstract]
7. Tsukuma H, Hiyama T, Tanaka S, et al.: Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 328 (25): 1797-801, 1993.  [PUBMED Abstract]
8. Chiaramonte M, Stroffolini T, Vian A, et al.: Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Cancer 85 (10): 2132-7, 1999.  [PUBMED Abstract]
9. Tagger A, Donato F, Ribero ML, et al.: Case-control study on hepatitis C virus (HCV) as a risk factor for hepatocellular carcinoma: the role of HCV genotypes and the synergism with hepatitis B virus and alcohol. Brescia HCC Study. Int J Cancer 81 (5): 695-9, 1999.  [PUBMED Abstract]
10. Yu MW, Chang HC, Liaw YF, et al.: Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives. J Natl Cancer Inst 92 (14): 1159-64, 2000.  [PUBMED Abstract]
11. Alpert ME, Hutt MS, Wogan GN, et al.: Association between aflatoxin content of food and hepatoma frequency in Uganda. Cancer 28 (1): 253-60, 1971.  [PUBMED Abstract]
12. Stillwagon GB, Order SE, Guse C, et al.: Prognostic factors in unresectable hepatocellular cancer: Radiation Therapy Oncology Group Study 83-01. Int J Radiat Oncol Biol Phys 20 (1): 65-71, 1991.  [PUBMED Abstract]
13. Izumi R, Shimizu K, Kiriyama M, et al.: Alpha-fetoprotein production by hepatocellular carcinoma is prognostic of poor patient survival. J Surg Oncol 49 (3): 151-5, 1992.  [PUBMED Abstract]
14. Yamashita Y, Takahashi M, Koga Y, et al.: Prognostic factors in the treatment of hepatocellular carcinoma with transcatheter arterial embolization and arterial infusion. Cancer 67 (2): 385-91, 1991.  [PUBMED Abstract]
15. Nakakura EK, Choti MA: Management of hepatocellular carcinoma. Oncology (Huntingt) 14 (7): 1085-98; discussion 1098-102, 2000.  [PUBMED Abstract]
16. Karl RC, Morse SS, Halpert RD, et al.: Preoperative evaluation of patients for liver resection. Appropriate CT imaging. Ann Surg 217 (3): 226-32, 1993.  [PUBMED Abstract]
17. Lo CM, Lai EC, Liu CL, et al.: Laparoscopy and laparoscopic ultrasonography avoid exploratory laparotomy in patients with hepatocellular carcinoma. Ann Surg 227 (4): 527-32, 1998.  [PUBMED Abstract]

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