General Information About Adult Primary Liver Cancer
Incidence and Mortality
Estimated new cases and deaths from liver and intrahepatic bile duct cancer in the United States in 2014:
- New cases: 33,190.
- Deaths: 23,000.
Hepatocellular carcinoma (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. HCC is the most common solid tumor worldwide and the third leading cause of cancer-related deaths.[3,4]
Both local extension of tumor and extent of liver function impairment affect prognosis and guide selection of treatment. Liver transplantation, surgical resection, and ablation techniques offer high rates of complete responses, and a potential for cure in early HCC. There are no large, robust, randomized studies that compare treatments considered effective for early stage disease, nor are there studies comparing these treatments with best supportive care. Best survivals are achieved when the HCC can be surgically excised (either by a transplantation or resection).
For patients with decompensated cirrhosis and a solitary lesion (<5 cm) or early multifocal disease (≤3 lesions, ≤3 cm), the best option is liver transplantation, but the limited availability of deceased liver donors restricts the use of this approach.
Surgical resection is usually performed in patients with localized HCC and sufficient functional hepatic reserve.
The etiology of HCC is likely multifactorial. Any chronic liver injury probably increases the risk of HCC. This risk seems elevated 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.[9,10][Level of evidence: 3iii]
Hepatitis B virus (HBV) infection and HCV infection appear to be the most significant causes of HCC worldwide. Chronic HBV infection is the leading cause of HCC in Asia and Africa, and HCV infection is the leading cause of HCC in Europe, Japan, and North America.[5,11]
The annual incidence of HCC in HBV carriers is 0.5% to 1% per year in noncirrhotic patients and 2.5% per year in cirrhotic patients. The relative risk of HCC is 100 (i.e., HBV carriers are 100 times more likely to develop HCC than uninfected persons).[12,13]
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 anti-HCV negative persons. HCC may occur in HCV-infected patients with bridging fibrosis even in the absence of overt cirrhosis. However, the risk is highest among those patients with HCV-related established cirrhosis, which has an incidence rate of HCC of 2% to 8% per year.
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 hepatitis C virus.
Recently, the risk factors associated with the 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 an incidence rate for HCC.
Hemochromatosis is also a significant risk factor for HCC and has an increased relative risk twenty times that of the normal population.
The incidence of HCC in stage IV primary biliary cirrhosis is approximately the same as in cirrhosis resulting from hepatitis C.
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 HBV carriers because it enhances the neoplastic risk threefold.
(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, no detailed investigation is required because most of these lesions will be cirrhotic nodules rather than HCC.[Level of evidence: 3iii] Close follow-up at 3-month intervals is recommended using the same technique that first documented the presence of the nodules.
For patients with liver nodules larger than 1 cm who are at risk for HCC, diagnosis should be established. The tests required to diagnose HCC may include radiology, biopsy, or both.
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 metastases from colon cancer. The finding of a mass in a liver with an elevated AFP does not automatically indicate HCC. If the AFP level is high, it can be used to monitor for recurrence.
In patients with cirrhosis, liver disease, or other risk factors for HCC, triple-phase, contrast-enhanced studies (dynamic computed tomography [CT]-scan or magnetic resonance imaging [MRI]) can be used to establish diagnosis of HCC for nodules larger than 1 cm.
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 an HCC of 1 to 3 cm in diameter and virtually diagnostic of HCC.[20-22][Level of evidence: 3ii] In these cases, the diagnosis of HCC may be considered established without the need for a second imaging modality, even in the absence of a biopsy confirmation.[5,22,23][Level of evidence: 3ii]
If, on the other hand, a first imaging modality, such as either 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 nodule larger than 1 cm remains uncharacterized in a patient at high risk for HCC (i.e., with only one or no classic enhancement pattern), a liver biopsy can be considered.[5,22]
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 nodules 1 cm or larger in high-risk patients.
Natural History and Prognostic Factors
The natural history of early tumors is poorly known because the majority of patients are treated. However, older reports have described 3-year survival rates of 13% to 21% without any specific treatment.[24,25] At present, only 10% to 23% of HCC patients may be surgical candidates for curative-intent treatment.[26,27] The 5-year overall survival rates for patients with early HCC who are undergoing liver transplant or liver resection are 44% to 78% and 27% to 70%, respectively.
The natural course of advanced-stage HCC is better known. Untreated patients with advanced disease usually survive less than 6 months. The 1-year and 2-year survival rates of untreated patients in 25 randomized clinical trials were 10% to 72% and 8% to 50%, respectively.
Unlike most patients with solid tumors, prognosis of HCC patients is affected not only by the tumor stage at presentation but also by the underlying liver function. The following are main prognostic factors for HCC patients:
Other PDQ summaries containing information related to adult primary liver cancer include the following:
- American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed November 24, 2014.
- 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]
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- Bosch FX, Ribes J, Díaz M, et al.: Primary liver cancer: worldwide incidence and trends. Gastroenterology 127 (5 Suppl 1): S5-S16, 2004. [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]
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- Llovet JM, Bruix J: Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 37 (2): 429-42, 2003. [PUBMED Abstract]
- Cammà C, Schepis F, Orlando A, et al.: Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 224 (1): 47-54, 2002. [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]
- 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]
- 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]
- Farinati F, Floreani A, De Maria N, et al.: Hepatocellular carcinoma in primary biliary cirrhosis. J Hepatol 21 (3): 315-6, 1994. [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]
- 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, 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]