General Information About Adult Primary Liver Cancer
Liver cancer includes two major types: hepatocellular carcinoma (HCC) and intrahepatic bile duct cancer. (Refer to the Cellular Classification of Adult Primary Liver Cancer section of this summary for additional, less-common variances; also refer to the Bile Duct Cancers PDQ summary for more information.)
Incidence and Mortality
Estimated new cases and deaths from liver and intrahepatic bile duct cancer in the United States in 2018:
- New cases: 42,220.
- Deaths: 30,200.
HCC is relatively uncommon in the United States, although its incidence is rising, principally in relation to the spread of hepatitis C virus (HCV) infection. Worldwide, HCC is the sixth most prevalent cancer and the third leading cause of cancer-related deaths.
The etiology of HCC is likely multifactorial. The following factors may increase the risk of HCC:
- Hepatitis B virus (HBV) infection and hepatitis C virus (HCV) infection: HBV and HCV infections appear to be the most significant causes of HCC worldwide. Chronic HBV infection is the leading cause of HCC in Asia and Africa. HCV infection is the leading cause of HCC in North America, Europe, and Japan.[4,5]
The annual incidence of HCC in HBV carriers is 0.5% to 1% per year in patients without cirrhosis and 2.5% per year in patients with cirrhosis. The relative risk of HCC is 100 (i.e., carriers of HBV are 100 times more likely to develop HCC than uninfected persons).[6,7]
In a single, prospective, population-based study that included 12,008 patients, the presence of anti-HCV positivity conferred a twentyfold increased risk of HCC compared with persons who were anti-HCV negative. HCC may occur in HCV-infected patients with bridging fibrosis, even in the absence of overt cirrhosis. However, the risk is highest among patients with HCV-related established cirrhosis, which has an incidence rate of HCC of 2% to 8% per year.
- Alcoholic cirrhosis: Several reports suggest that alcoholic cirrhosis is a risk factor for HCC. However, the true incidence of HCC in alcoholic cirrhosis is unknown because most epidemiology reports on this subject were published before the identification of HCV.
- Metabolic syndrome: The risk factors associated with metabolic syndrome, including insulin resistance, hypertension, dyslipidemia, and obesity, have been recognized as potential causes of nonalcoholic hepatosteatosis, cirrhosis, and HCC. However, no study to date has followed a sufficiently large group of these patients for long enough to describe the incidence of HCC caused by metabolic syndrome.
- Biliary cirrhosis: The incidence of HCC in stage IV primary biliary cirrhosis is approximately the same as in cirrhosis resulting from hepatitis C.
- Chronic liver injury: Chronic liver injury probably increases the risk of HCC, especially in patients who develop cirrhosis. The 5-year cumulative risk of developing HCC for patients with cirrhosis ranges between 5% and 30% and depends on etiology (highest in individuals with HCV infection), region or ethnicity (highest in Asians), and stage of cirrhosis.[12,13][Level of evidence: 3iii]
- Hemochromatosis: Hemochromatosis is a significant risk factor for HCC and has an increased relative risk twenty times that of the normal population.
- Aflatoxin B1: Aflatoxin B1 is produced by fungi of the Aspergillus species and is a common contaminant of grain, nuts, and vegetables in some parts of Asia and Africa. Aflatoxin B1 has also been implicated as a cofactor in the etiology of primary liver cancer in carriers of HBV because it increases the neoplastic risk threefold.
(Refer to the PDQ summary on Liver (Hepatocellular) Cancer Prevention for more information.)
(Refer to the PDQ summary on Liver (Hepatocellular) Cancer Screening for more information.)
For lesions that are smaller than 1 cm and are detected during screening in patients at high risk for HCC, further diagnostic evaluation is not required because most of these lesions will be cirrhotic lesions rather than HCC.[Level of evidence: 3iii] Close follow-up at 3-month intervals is a common surveillance strategy, using the same technique that first documented the presence of the lesions.
For patients with liver lesions larger than 1 cm who are at risk for HCC, a diagnosis should be established. The tests required to diagnose HCC may include imaging, biopsy, or both.
In patients with cirrhosis, liver disease, or other risk factors for HCC, and with lesions greater than 1 cm, triple-phase, contrast-enhanced studies (dynamic computed tomography [CT]-scan or magnetic resonance imaging [MRI]) can be used to establish a diagnosis of HCC.
A triple-phase CT or MRI assesses the entire liver in distinct phases of perfusion. Following the controlled administration of intravenous contrast media, the arterial and venous phases of perfusion are imaged.
During the arterial phase of the study, HCC enhances more intensely than the surrounding liver because the arterial blood in the liver is diluted by venous blood that does not contain contrast, whereas the HCC contains only arterial blood. In the venous phase, the HCC enhances less than the surrounding liver (which is referred to as the venous washout of HCC), because the arterial blood flowing through the lesion no longer contains contrast; however, the portal blood in the liver now contains contrast.
The presence of arterial uptake followed by washout in a single dynamic study is highly specific (95%–100%) for HCC of 1 to 3 cm in diameter and virtually diagnostic of HCC.[18-20][Level of evidence: 3ii] In these cases, the diagnosis of HCC may be established without the need for a second imaging modality, even in the absence of a biopsy confirmation.[4,20,21][Level of evidence: 3ii]
However, if a first imaging modality, such as a contrast-enhanced CT or MRI, is not conclusive, sequential imaging with a different modality can improve sensitivity for HCC detection (from 33% to 41% for either CT or MRI to 76% for both studies when performed sequentially) without a decrease in specificity.
If, despite the use of two imaging modalities, a lesion larger than 1 cm remains uncharacterized in a patient at high risk for HCC (i.e., with no or only one classic enhancement pattern), a liver biopsy can be considered.[4,20]
A liver biopsy may be performed when a diagnosis of HCC is not established by a dynamic imaging modality (three-phase CT or MRI) for liver lesions 1 cm or larger in high-risk patients.
Alpha-fetoprotein (AFP) levels
AFP is insufficiently sensitive or specific for use as a diagnostic assay. AFP can be elevated in intrahepatic cholangiocarcinoma and in some cases in which there are metastases from colon cancer. Finding a mass in the liver of a patient with an elevated AFP does not automatically indicate HCC. However, if the AFP level is high, it can be used to monitor for recurrence.
The natural course of early tumors is poorly known because most HCC patients are treated. However, older reports have described 3-year survival rates of 13% to 21% without any specific treatment.[22,23] At present, only 10% to 23% of patients with HCC may be surgical candidates for curative-intent treatment.[24,25] The 5-year overall survival (OS) rate for patients with early HCC who are undergoing liver transplant is 44% to 78%; and for patients undergoing a liver resection, the OS rate is 27% to 70%.
Liver transplantation, surgical resection, and ablation offer high rates of complete responses and a potential for cure in patients with early HCC.
The natural course of advanced-stage HCC is better known. Untreated patients with advanced disease usually survive less than 6 months. The survival rate of untreated patients in 25 randomized clinical trials ranged from 10% to 72% at 1 year and 8% to 50% at 2 years.
Unlike most patients with solid tumors, the prognosis of patients with HCC is affected by the tumor stage at presentation and by the underlying liver function. The following prognostic factors guide the selection of treatment:
- Anatomic extension of the tumor (i.e., tumor size, number of lesions, presence of vascular invasion, and extrahepatic spread).
- Performance status.
- Functional hepatic reserve based on the Child-Pugh score.[27,29,30]
Other PDQ summaries containing information related to primary liver cancer include the following:
- American Cancer Society: Cancer Facts and Figures 2018. Atlanta, Ga: American Cancer Society, 2018. Available online. Last accessed August 3, 2018.
- Altekruse SF, McGlynn KA, Reichman ME: Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 27 (9): 1485-91, 2009. [PUBMED Abstract]
- Forner A, Llovet JM, Bruix J: Hepatocellular carcinoma. Lancet 379 (9822): 1245-55, 2012. [PUBMED Abstract]
- Bruix J, Sherman M; American Association for the Study of Liver Diseases: Management of hepatocellular carcinoma: an update. Hepatology 53 (3): 1020-2, 2011. [PUBMED Abstract]
- Bosch FX, Ribes J, Borràs J: Epidemiology of primary liver cancer. Semin Liver Dis 19 (3): 271-85, 1999. [PUBMED Abstract]
- Beasley RP, Hwang LY, Lin CC, et al.: Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet 2 (8256): 1129-33, 1981. [PUBMED Abstract]
- Beasley RP: Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer 61 (10): 1942-56, 1988. [PUBMED Abstract]
- Sun CA, Wu DM, Lin CC, et al.: Incidence and cofactors of hepatitis C virus-related hepatocellular carcinoma: a prospective study of 12,008 men in Taiwan. Am J Epidemiol 157 (8): 674-82, 2003. [PUBMED Abstract]
- Lok AS, Seeff LB, Morgan TR, et al.: Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology 136 (1): 138-48, 2009. [PUBMED Abstract]
- Hessheimer AJ, Forner A, Varela M, et al.: Metabolic risk factors are a major comorbidity in patients with cirrhosis independent of the presence of hepatocellular carcinoma. Eur J Gastroenterol Hepatol 22 (10): 1239-44, 2010. [PUBMED Abstract]
- Farinati F, Floreani A, De Maria N, et al.: Hepatocellular carcinoma in primary biliary cirrhosis. J Hepatol 21 (3): 315-6, 1994. [PUBMED Abstract]
- 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 21 (1): 77-82, 1995. [PUBMED Abstract]
- Mair RD, Valenzuela A, Ha NB, et al.: Incidence of hepatocellular carcinoma among US patients with cirrhosis of viral or nonviral etiologies. Clin Gastroenterol Hepatol 10 (12): 1412-7, 2012. [PUBMED Abstract]
- Jaskiewicz K, Banach L, Lancaster E: Hepatic siderosis, fibrosis and cirrhosis: the association with hepatocellular carcinoma in high-risk population. Anticancer Res 17 (5B): 3897-9, 1997 Sep-Oct. [PUBMED Abstract]
- Sun Z, Lu P, Gail MH, et al.: Increased risk of hepatocellular carcinoma in male hepatitis B surface antigen carriers with chronic hepatitis who have detectable urinary aflatoxin metabolite M1. Hepatology 30 (2): 379-83, 1999. [PUBMED Abstract]
- Furuya K, Nakamura M, Yamamoto Y, et al.: Macroregenerative nodule of the liver. A clinicopathologic study of 345 autopsy cases of chronic liver disease. Cancer 61 (1): 99-105, 1988. [PUBMED Abstract]
- Brunello F, Cantamessa A, Gaia S, et al.: Radiofrequency ablation: technical and clinical long-term outcomes for single hepatocellular carcinoma up to 30 mm. Eur J Gastroenterol Hepatol 25 (7): 842-9, 2013. [PUBMED Abstract]
- Leoni S, Piscaglia F, Golfieri R, et al.: The impact of vascular and nonvascular findings on the noninvasive diagnosis of small hepatocellular carcinoma based on the EASL and AASLD criteria. Am J Gastroenterol 105 (3): 599-609, 2010. [PUBMED Abstract]
- Khalili K, Kim TK, Jang HJ, et al.: Optimization of imaging diagnosis of 1-2 cm hepatocellular carcinoma: an analysis of diagnostic performance and resource utilization. J Hepatol 54 (4): 723-8, 2011. [PUBMED Abstract]
- Sangiovanni A, Manini MA, Iavarone M, et al.: The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis. Gut 59 (5): 638-44, 2010. [PUBMED Abstract]
- Khalili K, Kim TK, Jang HJ, et al.: Implementation of AASLD hepatocellular carcinoma practice guidelines in North America: two years of experience. [Abstract] Hepatology 48 (Suppl 1): A-128, 362A, 2008.
- Barbara L, Benzi G, Gaiani S, et al.: Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumor growth rate and patient survival. Hepatology 16 (1): 132-7, 1992. [PUBMED Abstract]
- Ebara M, Ohto M, Shinagawa T, et al.: Natural history of minute hepatocellular carcinoma smaller than three centimeters complicating cirrhosis. A study in 22 patients. Gastroenterology 90 (2): 289-98, 1986. [PUBMED Abstract]
- Shah SA, Smith JK, Li Y, et al.: Underutilization of therapy for hepatocellular carcinoma in the medicare population. Cancer 117 (5): 1019-26, 2011. [PUBMED Abstract]
- Sonnenday CJ, Dimick JB, Schulick RD, et al.: Racial and geographic disparities in the utilization of surgical therapy for hepatocellular carcinoma. J Gastrointest Surg 11 (12): 1636-46; discussion 1646, 2007. [PUBMED Abstract]
- Dhir M, Lyden ER, Smith LM, et al.: Comparison of outcomes of transplantation and resection in patients with early hepatocellular carcinoma: a meta-analysis. HPB (Oxford) 14 (9): 635-45, 2012. [PUBMED Abstract]
- Okuda K, Ohtsuki T, Obata H, et al.: Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer 56 (4): 918-28, 1985. [PUBMED Abstract]
- Llovet JM, Bruix J: Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 37 (2): 429-42, 2003. [PUBMED Abstract]
- Llovet JM, Brú C, Bruix J: Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 19 (3): 329-38, 1999. [PUBMED Abstract]
- A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 28 (3): 751-5, 1998. [PUBMED Abstract]