AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Hepatocellular carcinoma (HCC) is a primary malignancy of the hepatocyte, generally leading to death within 6-20 months. Hepatocellular carcinoma frequently arises in the setting of cirrhosis, appearing 20-30 years following the initial insult to the liver. However, 25% of patients have no history or risk factors for the development of cirrhosis. The extent of hepatic dysfunction limits treatment options, and as many patients die of liver failure as from tumor progression.

Although it is currently one of the most common worldwide causes of cancer death, a major impact on the incidence of hepatocellular carcinoma should be achieved through current vaccination strategies for hepatitis B virus (HBV) infection, screening and treatment for hepatitis C virus (HCV) infections, and from the reduction of alcoholic liver disease. However, because the latency period from hepatic damage to hepatocellular carcinoma development is very long, it may be many years until the incidence of hepatocellular carcinoma decreases as a result of these interventions.

Pathophysiology

Tumors are multifocal within the liver 75% of the time. Late in the disease, metastases may develop in the lung, portal vein, periportal nodes, bone, or brain (see Media files 1 and 4).

Frequency

United States

Although hepatocellular carcinoma is uncommon, comprising only 2% of all malignancies, since the mid-1980s the incidence of hepatocellular carcinoma has been rising at an alarming rate.^{1, 2, 3} The age-adjusted incidence rates increased 2-fold between 1980 and 1998. Much of this increase is likely due to hepatitis C infection, a known risk factor for hepatocellular carcinoma.⁴ The American Cancer Society projects that 19,160 new cases of hepatocellular carcinoma and intrahepatic bile duct cancers were expected to be diagnosed in 2007 with 13,650 cases in men and 5,510 cases in women. An estimated 16,780 patients (11,280 men and 5,500 women) were expected to die of hepatocellular carcinoma and intrahepatic bile duct cancer in 2007.⁵  

International

Hepatocellular carcinoma is the fifth most common cancer in men and the eighth most common cancer in women worldwide. An estimated 560,000 new cases are diagnosed annually. The incidence of hepatocellular carcinoma worldwide varies according to the prevalence of hepatitis B and C infections. Areas such as Asia and sub-Saharan Africa with high rates of infectious hepatitis have incidences as high as 120 cases per 100,000.⁶

Mortality/Morbidity

• Cure, usually through surgery, is possible in fewer than 5% of all patients.
• Median survival from time of diagnosis is generally 6 months. Length of survival depends largely on the extent of cirrhosis in the liver; cirrhotic patients have shorter survival times and more limited therapeutic options; portal vein occlusion, which occurs commonly, portends an even shorter survival.
• Complications from hepatocellular carcinoma are those of hepatic failure; death occurs from cachexia, variceal bleeding, or (rarely) tumor rupture and bleeding into the peritoneum.

Race

Hepatocellular carcinoma is most commonly found among Asian persons, due to childhood infections with hepatitis B. However, due to the implementation of childhood hepatitis B vaccination programs in many Asian countries, a decrease in the incidence of hepatocellular carcinoma among Asians is expected.

Sex

• Hepatocellular carcinoma occurs more commonly in men than in women.
• In the United States, 74% of hepatocellular carcinoma cases occur in men.
• In high-risk areas (China, sub-Saharan Africa, Japan), the difference in incidence between the sexes is more pronounced, with male-to-female ratios as high as 8:1.

Age

• Age at diagnosis varies widely according to geographic distribution.
• In the United States and Europe, the median age at diagnosis is 65 years. Hepatocellular carcinoma is rarely diagnosed in persons younger than 40 years. However, between 1975 and 1998, the 45- to 49-year age group had the highest rate, a 3-fold increase in the incidence of hepatocellular carcinoma.
• In Africa and Asia, age at diagnosis is substantially younger, occurring in the fourth and fifth decades of life, respectively. Diagnosis at a younger age is thought to reflect the natural history of hepatitis B and C related hepatocellular carcinoma.⁷

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Patients generally present with symptoms of advancing cirrhosis.

• Pruritus
• Jaundice
• Splenomegaly
• Variceal bleeding
• Cachexia
• Increasing abdominal girth (portal vein occlusion by thrombus with rapid development of ascites)
• Hepatic encephalopathy
• Right upper quadrant pain (uncommon)

Physical

• Jaundice
• Ascites
• Hepatomegaly
• Alcoholic stigmata (Dupuytren contracture, spider angiomata)
• Asterixis
• Pedal edema
• Periumbilical collateral veins
• Enlarged hemorrhoidal veins

Causes

• Cirrhosis: In general, cirrhosis of any etiology is the major risk factor for hepatocellular carcinoma.^{8, 9} About 80% of patients with newly diagnosed hepatocellular carcinoma have preexisting cirrhosis. Major causes of cirrhosis in the United States are attributed to alcohol, hepatitis C infection, and hepatitis B infection.⁴
• Alcohol
• • In the United States, about 30% of hepatocellular carcinoma cases are thought to be related to excessive alcohol use. Chronic alcohol use (>80 g/d or >6-7 drinks per day) for more than 10 years increases risk of hepatocellular carcinoma 5-fold.
  • Approximately 50% of US patients have histories of alcohol abuse. As many as 50% of alcoholics may have subclinical hepatocellular carcinoma at autopsy.
  • The risk of hepatocellular carcinoma is greater once the patient stops drinking alcohol, because heavy drinkers do not survive long enough to develop cancer.
  • The risk of hepatocellular carcinoma in patients with decompensated alcoholic cirrhosis is approximately 1% per year.
• Hepatitis B virus
• • Global incidence of chronic HBV infection is estimated to be 350 million persons; chronic HBV infection is the most common cause of hepatocellular carcinoma worldwide. In the United States, about 20% of hepatocellular carcinoma cases are thought to be related to chronic hepatitis B infection.
  • Chronic infection in the setting of cirrhosis increases the risk of hepatocellular carcinoma 1000-fold.
  • The mechanism by which the hepatitis B virus causes hepatocellular carcinoma is thought to be from a combination of chronic inflammation and integration of the viral genome into the host DNA.
  • In a Taiwanese study, hepatitis B vaccination in newborns and children has already shown a 75% decrease in the incidence of hepatocellular carcinoma in children.¹⁰ Thus far, 135 countries have added hepatitis B vaccination to their routine vaccination programs. It is anticipated that with implementation of worldwide vaccination, the incidence of hepatitis B-related hepatocellular carcinoma is going to decrease.
  • See related CME at Understanding Resistance in Hepatitis B--Clinical Implications and Strategies in the Management of Chronic Hepatitis B.
• Hepatitis C virus
• • HCV is a global pandemic affecting 170 million persons. HCV infection results in a higher rate of chronic infection compared to HBV infection (approximately 80% of infected subjects).
  • It has become the most common cause of hepatocellular carcinoma in Japan and Europe, and it is also responsible for the recent increased incidence in the United States.¹ About 2.7 million Americans have chronic HCV infection. In the United States, about 30% of hepatocellular carcinoma cases are thought to be related to HCV infection. Some 5-30% of individuals with HCV infection develop chronic liver disease. In this group, about 30% progress to cirrhosis, and in these, about 1-2% per year develop hepatocellular carcinoma.
  • The lifetime risk of hepatocellular carcinoma in patients with HCV is approximately 5%, appearing 30 years after infection.
  • Co-infection with HBV further increases the risk; many patients are co-infected with both viruses. Alcohol use in the setting of chronic HCV doubles the risk of hepatocellular carcinoma compared with HCV infection alone.
  • Recent studies suggest that antiviral treatment of chronic HCV infections may reduce the risk of hepatocellular carcinoma significantly.
  • See related CME at Diabetes May Increase Risk for Hepatocellular Carcinoma in Patients With Hepatitis C.
• Hemochromatosis: Patients with hemochromatosis, especially in the presence of cirrhosis, are at an increased risk of developing hepatocellular carcinoma. Hepatocellular carcinoma accounts for about 30% of all iron-related deaths in hemochromatosis.
• Aflatoxin: This hepatic carcinogen is a byproduct of fungal contamination of foodstuffs in sub-Saharan Africa and East and Southeast Asia. It causes DNA damage and mutations of the p53 gene. Humans are exposed to aflatoxin through the ingestion of moldy foods found in susceptible grains. Dietary levels in endemic areas correlate directly with incidence of hepatocellular carcinoma.
• Rare associations: These include primary biliary cirrhosis, androgenic steroids, primary sclerosing cholangitis, 1-antitrypsin deficiency, Thorotrast radioactive contrast, oral contraceptives, and porphyria cutanea tarda. Obesity and diabetes have been implicated as risk factors for hepatocellular carcinoma, most likely through the development of nonalcoholic steatohepatitis (NASH).^{11, 2, 12, 13} In the analysis of a large managed care database, the incidence of hepatocellular carcinoma linked to nonalcoholic fatty liver disease rose by 10 times from 0.03-0.46 per 100,000 between the years 1997 and 2005.¹⁴

Also see Modifiable Risk Factors May Reduce Death from Cancers of the Digestive System.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Dysplastic nodules in cirrhosis
Fibrous nodular hyperplasia
Metastatic disease
Primary hepatic lymphoma

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Expect total bilirubin, aspartate aminotransferase (AST), alkaline phosphatase, albumin, and prothrombin time to show results consistent with cirrhosis.
• Alpha-fetoprotein (AFP) is elevated in 75% of cases.
• • The level of elevation correlates inversely with prognosis.
  • An elevation of greater than 400 ng/mL predicts for hepatocellular carcinoma with specificity greater than 95%. In the setting of a growing mass, cirrhosis, and the absence of acute hepatitis, many centers use a level greater than 1000 ng/mL as presumptive evidence of hepatocellular carcinoma (without biopsy). Alpha-fetoprotein (AFP) is inadequate for screening purposes because of the high rate of false positives in active hepatitis; it only begins to rise when vascular invasion occurs.¹⁵

Imaging Studies

• Obtain liver imaging using ultrasonography, CT scanning, or MRI (see Media file 3). When performed for suspected hepatocellular carcinoma due to a rising AFP, each test has a 70-85% chance of finding a solitary lesion; sensitivity is higher with multiple tumors.
• Ultrasonography is the least expensive choice for screening, but it is highly operator-dependent. A suspicious lesion on a sonogram generally requires additional imaging studies to confirm the diagnosis and the stage of the tumor. Sensitivity of ultrasonography for detection of small nodules is low. An advantage is that Doppler imaging can be performed at the same time to determine the patency of the portal vein.
• Use the triphasic technique when performing CT scanning (ie, without contrast, then with early [arterial] and late [portal] imaging). The addition of arterial phase imaging to conventional CT scanning increases the number of tumor nodules detected. Unfortunately, in nodular cirrhotic livers, the sensitivity of CT scanning for detecting hepatocellular carcinoma is low. CT scanning has the added benefit of detecting extrahepatic disease, especially lymphadenopathy.
• MRI may detect smaller lesions and can also be used to determine flow in the portal vein. The overall sensitivity of MRI is thought to be similar to that of triphasic CT scanning. However, in patients with nodular cirrhotic livers, MRI has been shown to have better sensitivity and specificity. High cost and restricted access to MRIs makes its widespread use limited.
• Angiography shows characteristic tumor blush in hepatocellular carcinoma lesions. Less invasive imaging with CT scan and MRI has decreased the necessity for this mode of imaging. Angiography is still used for chemoembolization, one of the treatment options for hepatocellular carcinoma.
• Chest radiography may demonstrate pulmonary metastases (see Media file 5).
• Bone scanning and head CT scanning are of low yield in the absence of specific symptoms.
• PET scan has been evaluated in the experimental setting, but, to date, its role is uncertain. Routine use of PET scan for diagnosis or staging of hepatocellular carcinoma is not recommended.

Procedures

• Biopsy is frequently necessary in order to make the diagnosis. In general, core biopsy is favored over fine needle biopsy since larger amounts of tissue, often with normal surrounding parenchyma, can be obtained.
• Controversy exists regarding the potential risk of tumor seeding along the needle tract. Some studies report a small increase in risk (approximately 1/1000), while others show no difference. Regardless, potential risks and complications should be considered before performing a biopsy.
• Biopsy may be omitted in a clinical setting of a growing mass in a cirrhotic liver (>2 cm) noted on 2 coincident imaging techniques with at least one imaging showing contrast enhancement. Likewise, a growing mass in a cirrhotic liver on one imaging modality with an associated AFP level greater than 500-1000 ng/mL is clinically diagnostic of hepatocellular carcinoma. The need for biopsy should be carefully evaluated, especially if the risk for complications is high.
• Biopsy is generally obtained percutaneously under ultrasonographic or CT guidance. Prior to obtaining biopsy, large-volume paracentesis may be useful in patients with massive ascites; similarly, platelet transfusion may be necessary in patients with cirrhosis with severe thrombocytopenia (<50,000). Bleeding risk does not correlate with elevations in prothrombin time.
• Lesions that are 2-3 cm or smaller may be dysplastic nodules in a cirrhotic background. These are probably premalignant, and obtaining a biopsy is especially important to distinguish them from hepatocellular carcinoma. False-negative rates as high as 30-40% have been reported for biopsied tumors smaller than 2 cm in size.
• Using laparoscopic guidance may make obtaining a percutaneous biopsy easier. Laparoscopy allows visualization of the liver to evaluate the extent of cirrhosis if surgery is being contemplated.
• Obtaining a biopsy may be unnecessary in patients who will undergo resection regardless of diagnosis.

Histologic Findings

Histology is quite variable, ranging from well-differentiated tumors to anaplastic tumors. The fibrolamellar subtype is associated with a better prognosis, possibly because it is not associated with cirrhosis and is more likely to be resectable. The presence of intracellular bile or staining for AFP may be helpful in distinguishing hepatocellular carcinoma from other hepatic malignancies (eg, cholangiocarcinoma). Immunohistochemistry using the marker Hep-Par 1 may aid in the diagnosis. Aberrations of chromosome 1 and 8 are common features of hepatocellular carcinoma that can be detected by fluorescent in situ hybridization (FISH) technique. The role of FISH in the diagnosis of hepatocellular carcinoma is still under investigation.

Staging

The tumor, node, and metastases (TNM) staging system, while widely accepted, is really only useful in patients who undergo surgical resection. This is a small minority of patients.

Since most patients are unresectable, and prognosis actually depends more upon the state of the liver rather than the size of the tumor, several staging systems have been evaluated that incorporate clinical features of the liver and the patient, such as ascites, portal vein involvement, and performance status. One such system is the CLIP (Cancer of the Liver Italian Program) scoring system, which assigns a cumulative prognostic score ranging from 0-6 based upon Child-Pugh stage, tumor morphology, alpha-fetoprotein level, and portal vein thrombosis, which can predict median survival time.¹⁶ Below is a summary of the TNM staging criteria and the CLIP scoring system.

• TNM staging criteria for hepatocellular carcinoma
• • T1 - Solitary tumor without vascular invasion
  • T2 - Solitary tumor with vascular invasion or multiple tumors none more than 5 cm
  • T3 - Multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic vein(s)
  • T4 - Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum
  • N0 - Indicates no nodal involvement
  • N1 - Indicates regional nodal involvement
  • M0 - Indicates no distant metastasis
  • M1 - Indicates metastasis presence beyond the liver
• Stage grouping
• • Stage I = T1 + N0 + M0
  • Stage II = T2 + N0 + M0
  • Stage IIIA = T3 + N0 + M0
  • Stage IIIB = T4 + N0 + M0
  • Stage IIIC = TX + N1 + M0
  • Stage IVB = TX + NX + M1
• CLIP scoring system: Score of 0-2 is assigned for each of the 4 features listed below; cumulative score ranging from 0-6 is the CLIP score.
• • Child-Pugh stage
  • • Stage A = 0
    • Stage B = 1
    • Stage C = 2
  • Tumor morphology
  • • Uninodular and extension less than 50% = 0
    • Multinodular and extension less than 50% = 1
    • Massive and extension greater than 50% = 2
  • Alpha-fetoprotein
  • • Less than 400 = 0
    • Greater than 400 = 1
  • Portal vein thrombosis
  • • Absent = 0
    • Present = 1
  • Estimated survival based on CLIP score: Patients with a total CLIP score of 0 have an estimated survival of 31 months; those with score of 1, about 27 months; score of 2, 13 months; score of 3, 8 months; and scores 4-6, approximately 2 months.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Available treatment options depend on the size, number, and location of tumors; presence or absence of cirrhosis; operative risk based on extent of cirrhosis and comorbid diseases; overall performance status; patency of portal vein; and presence of metastatic disease.^{17, 18, 19}

Before instituting definitive therapy, it is best to treat the complications of cirrhosis with diuretics, paracentesis for ascites, lactulose for encephalopathy, ursodiol for pruritus, sclerosis or banding for variceal bleeding, and antibiotics for spontaneous bacterial peritonitis.

Surgical resection and liver transplantation are the only chances of cure but have limited applicability. The main prognostic factors for resectability are tumor size and liver function. Only about 5% of hepatocellular carcinoma patients are suitable for transplantation; these patients may have a 5-year survival of greater than 75% with tumor recurrence rates as low as 15% at 5 years.²⁰ Other local therapies are chemoembolization, ethanol ablation, radiofrequency ablation, cryoablation, and radiotherapy. Patients whose disease is downstaged following chemoembolization may be eligible for transplantation. Systemic treatment with chemotherapy may be used for advanced disease.

• Systemic chemotherapy
• • For patients with advanced hepatocellular carcinoma who are not candidates for surgical resection, liver transplantation, or localized tumor ablation, systemic chemotherapy remains the mainstay of therapy. Unfortunately, hepatocellular carcinoma is a relatively chemotherapy-resistant tumor; therefore, outcomes using this mode of treatment are unsatisfactory. Resistance to chemotherapy may be caused by the universal expression of the multidrug resistance gene protein on the surface of the malignant cells, leading to active efflux of chemotherapeutic agents. Chemotherapy is usually not well tolerated and seems to be less efficacious in patients with hepatocellular carcinoma with underlying hepatic dysfunction. Younger patients with well-compensated cirrhosis due to chronic hepatitis B or C infections have better outcomes with chemotherapy than older patients with alcoholic cirrhosis and other comorbid diseases.
  • The most active single agent drugs tested have been doxorubicin, cisplatin, and fluorouracil. Response rates are about 10%, and treatment shows no clear impact on overall survival.^{21, 18} More recently, gemcitabine and capecitabine have been evaluated in clinical trials; response rates have been low and short term.
  • Various combination chemotherapy regimens have also been studied. Recently, cisplatin-based combination regimens, such as gemcitabine and oxaliplatin, have shown improved response rates around 20%, but to date, no survival advantage as compared to supportive care alone has been shown. No difference seems to exist in response rates between 2- or 3-drug regimens. Moreover, some of these combination regimens cause considerable toxicity.
  • Chemoimmunotherapy uses a combination of chemotherapy and immunomodulatory agents, such as interferon-alpha, to try to achieve better tumor response rates. Immunotherapy has had encouraging results in patients with certain types of cancers such as renal cell carcinoma and melanoma. PIAF is a combination of cisplatin, interferon-alpha, doxorubicin, and infusional 5-fluorouracil that is associated with a response rate of 26%, which is higher than the response rates with single chemotherapy agents. Although overall median survival is longer with PIAF than single-agent doxorubicin, treatment-related toxicity is significant. The best candidates for this therapy are young patients without liver cirrhosis and normal bilirubin levels.²²
  • Antiangiogenesis agents (ie, bevacizumab), which work by disrupting the formation of blood vessels that feed tumors, are a new class of drugs that may prove to be of benefit in the treatment of hepatocellular carcinoma. The highly vascular nature of hepatocellular carcinoma tumors suggested that therapy with an antiangiogenesis agent might be effective. Bevacizumab by itself, however, is of limited clinical use. The combination of bevacizumab with gemcitabine and oxaliplatin, though, produced a 20% response rate with an additional 27% of patients who had stable disease.²³ 
  • Sorafenib, a multitargeted oral kinase inhibitor, has recently been shown in a phase III trial to prolong survival in patients with hepatocellular carcinoma.²⁴ This agent, which targets various pathways, including VEGFR, PDGFR, KIT, FLT-3, and RET, was compared to placebo in a trial of 602 patients. Median survival was prolonged significantly to 10.7 from 7.9 months, and time to progression was 5.5 months, compared with 2.8 in the placebo group. Currently, this is the only FDA-approved antineoplastic for hepatocellular carcinoma. The recently revised National Comprehensive Cancer Network (NCCN) guidelines for hepatocellular carcinoma recommend sorafenib as a treatment option at several points in the treatment algorithm.¹⁷ Sunitinib is another multitargeted tyrosine kinase inhibitor with reported activity in hepatocellular carcinoma,²⁵ Erlotinib, an oral epidermal growth factor (EGF) receptor tyrosine kinase inhibitor, has also shown some activity against hepatocellular carcinoma when used alone or in combination with bevacizumab.^{26, 27} A recent report has suggested that the mTOR inhibitor sirolimus may have benefit in the treatment of both cholangiocellular carcinoma and hepatocellular carcinoma.²⁷
  • Chemoembolization is the delivery of high concentrations of chemotherapeutic agents directly to the hepatocellular carcinoma tumor via the hepatic artery, which provides the tumor with most of its blood supply. The remainder of the liver may be spared because it can rely on the portal vein for its blood supply.²⁸
  • Embolizing agents such as cellulose, microspheres, lipoidal, and gelatin foam particles are used to deliver intra-arterial chemotherapy (mitomycin, doxorubicin, cisplatin) to the tumor via the hepatic artery.
  • Morbidity from this procedure is greatly dependent on the extent of cirrhosis. In general, patients with portal vein thrombosis, encephalopathy, or biliary obstruction are not candidates for chemoembolization.²⁹
  • Response rates of 60-80% are seen. In addition, 2 recent clinical trials from Spain and Hong Kong showed a modest survival benefit with the use of doxorubicin (Adriamycin) or cisplatin with embolization as compared to supportive care only in patients with unresectable tumors.^{30, 31, 32}
• See related CME at Diagnosis and Management of Hepatocellular Carcinoma.

Surgical Care

• Partial hepatectomy
• • In the United States, resection is possible in only 5% of patients. In general, solitary hepatocellular carcinoma lesions confined to the liver without vascular invasion with well-preserved hepatic function have the best outcomes. Although there are no strict criteria in terms of tumor size, many surgeons use less than 5 cm as their cutoff.
  • Five-year survival rates for resectable lesions vary widely from 30% to as high as 90% for very early stage hepatocellular carcinoma lesions.^{33, 34} Fibrolamellar hepatocellular carcinoma may have a better prognosis for survival after surgical resection because of a more favorable size, predominantly left lobe location, and the absence of cirrhosis in the unaffected portion of the liver.
  • Appropriate evaluation of patients prior to resection is crucial since intraoperative mortality is doubled in cirrhotic versus noncirrhotic patients. Preoperative laparoscopic inspection aids in diagnosing both the tumor and extent of cirrhosis.
• Transplantation
• • Many patients are not candidates for partial hepatectomy due to extent of underlying liver disease. Some of these patients are good candidates for liver transplantation since it has the potential for eliminating the cancer as well as curing the underlying liver disease.
  • Orthotopic liver transplantation can be considered for patients who meet the Milan criteria—one tumor less than 5 cm or up to 3 tumors all less than 3 cm. These highly selected patients have excellent survival rates, similar to those of patients who undergo liver transplantation for end-stage liver disease without hepatocellular carcinoma.^{35, 36, 37, 38}
  • Although availability of donor organs is still limited, the Organ Procurement and Transplantation Network (OPTN) and the United Network for Organ Sharing (UNOS) have recognized the urgency of proceeding to transplantation in patients with limited stage hepatocellular carcinoma. Over the past 5 years, revision of the UNOS policy has established medical criteria by which a patient with early/small hepatocellular carcinoma can be assigned additional priority for liver allocation so as to increase the likelihood of a favorable transplant outcome. This has resulted in shorter wait times to transplantation and better overall outcomes. Bridging therapy with local therapies, such as chemoembolization or radiofrequency ablation (RFA), is sometimes considered for patients on the transplant waiting list.
• Local tumor ablation
• • Intratumoral injections of ethanol or acetic acid, heat (via radiofrequency, microwave, or laser ablation), or cold (cryoablation with liquid nitrogen) may be used to locally control tumors smaller than 4-5 cm. These techniques are frequently performed percutaneously as outpatient procedures. In general, these procedures are reserved for patients who do not meet criteria for surgical resection yet are candidates for a liver-directed procedure based on the presence of limited liver-only disease.
  • Radiofrequency ablation (RFA) is the delivery of radiofrequency thermal energy to the hepatocellular carcinoma lesion causing necrosis of the tumor. During RFA, a high frequency alternating current is delivered from the tip of an electrode into the surrounding tissue. The ions within the tissue attempt to follow the direction of the alternating current resulting in friction and eventual heating of the tissue. As tissue temperature elevates above 60°C, tumor cells begin to die resulting in an area of tumor necrosis. The needle electrode is advanced into the hepatocellular carcinoma lesion usually via a percutaneous route with the guidance of ultrasonography. The procedure can also be performed surgically via laparoscopy or laparotomy.
  • RFA is usually used for treatment of tumors less than 4 cm in size. For small tumors, studies show good initial local tumor control with an average local recurrence rate of 5-6% within the first 20 months. The treatment of larger tumors results in much higher rates of local recurrence. Unfortunately, a significant proportion of patients eventually develop clinically detectable hepatic or extrahepatic disease from their preexisting micrometastatic lesions. RFA is usually well-tolerated, but complications including fever, pain, bleeding, pleural effusion, hematoma, and intermittent transaminitis among others have been reported.³⁹
  • Percutaneous ethanol or acetic acid ablation is reserved for patients with small tumors; however, in many areas, the ease and efficacy of RFA has now replaced these older techniques. Radiation therapy is limited by dose-related radiation hepatitis, which precludes the administration of external beam radiation in doses effective for tumor eradication. Doses of 2500 cGy may be used for palliative measures.
  • CyberKnife system is a new technology that uses a combination of robotics and image guidance to deliver concentrated and highly focused beams of radiation to the tumor while minimizing radiation exposure to the surrounding healthy liver tissue. CyberKnife stereotactic radiosurgery is a promising new treatment tool for localized hepatocellular carcinoma lesions. Currently, its availability is limited to a few medical centers, and long-term efficacy for hepatocellular carcinoma lesions is yet to be determined.

Consultations

• Hepatobiliary surgeon
• Oncologist
• Interventional radiologist
• Interventional gastroenterologist

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• Multimedia
• References

Drug Category: Antineoplastic agents

Few options are available for the systemic therapy of hepatocellular carcinoma (see Treatment).

Drug Category: Immunosuppressant agents

Agents that inhibit signal transduction pathways may be of benefit.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

Monitor the progression of disease or adequacy of treatment with imaging studies every 2-3 months and LFTs and AFP monthly or as appropriate for the stage of disease and patient's performance status. These interventions, however, have little or no impact on prognosis for survival and therefore should be performed in accordance with the patient's functional status.

Deterrence/Prevention

Patients should avoid alcohol and other hepatic toxins because prognosis is related to worsening cirrhosis and tumor stage.

Complications

Symptoms of hepatic failure may signify tumor recurrence and/or progression.

Prognosis

Overall prognosis for survival depends on the extent of cirrhosis and tumor stage, which then determine the appropriate treatment. Patients able to undergo a curative resection have a median survival of as long as 4 years; patients who present when they are too ill to be treated have a median survival of 3 months.⁴⁰

Patient Education

For excellent patient education resources, visit eMedicine's Hepatitis Center and Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient education articles, Cirrhosis, Hepatitis B, Hepatitis C, and Liver Transplant.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Consider hepatocellular carcinoma in any person with possible risk factors who develops symptoms of liver disease, such as unexplained jaundice, increased abdominal girth, or pruritus.
• Family members of patients with hepatitis B infections should undergo screening for the virus.
• Consider screening of patients with cirrhosis, especially those with hepatitis C infection.

Special Concerns

• Screening for hepatocellular carcinoma
• • Despite the widespread use of screening and surveillance programs for hepatocellular carcinoma, the efficacy and cost-effectiveness of screening programs for at-risk patients is unclear.⁴¹
  • In general, the annual incidence of developing hepatocellular carcinoma in the setting of cirrhosis is approximately 1-4%. Screening studies have shown that, although lesions may be discovered at an earlier stage, the lack of curative treatment options in patients with cirrhosis may not lead to improvements in survival.
  • Patients with chronic hepatitis B without cirrhosis have a much lower annual incidence of developing hepatocellular carcinoma of 0.46%. The incidence of hepatocellular carcinoma in patients with chronic hepatitis C without cirrhosis is even lower. Screening programs using AFP and an imaging modality in patients with hepatitis B or C without cirrhosis is not cost-effective given the low incidence of hepatocellular carcinoma in these patients and the high cost of imaging techniques.
  • Survival advantage with screening in these at-risk populations has not been demonstrated. The retrospective screening studies that have shown modest survival advantages are confounded by lead-time and length-time bias.
  • If screening is to be undertaken, AFP should not be used alone as a screening test. Instead, AFP should be combined with an imaging modality (ultrasonography, CT scan) to improve sensitivity and specificity.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Hepatic carcinoma, primary. Dilated collateral superficial abdominal veins in a 67-year-old man with cirrhosis, hepatocellular carcinoma (HCC), and portal vein occlusion.
	View Full Size Image
Media type:  Photo

Media file 2:  Hepatic carcinoma, primary. Large multifocal hepatocellular carcinoma (HCC) in an 80-year-old man without cirrhosis.
	View Full Size Image
Media type:  CT

Media file 3:  Hepatic carcinoma, primary. Noncontrast CT scans at 1 day and 3 months following chemoembolization with doxorubicin/Ethiodol Gelfoam.
	View Full Size Image
Media type:  CT

Media file 4:  Hepatic carcinoma, primary. Unusual location of a bone metastasis from hepatocellular carcinoma (HCC).
	View Full Size Image
Media type:  MRI

Media file 5:  Hepatic carcinoma, primary. Plain radiograph immediately following chemoembolization, demonstrating catheter placement and Ethiodol enhancement of tumors.
	View Full Size Image
Media type:  X-RAY

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• Multimedia
• References

1. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. Mar 11 1999;340(10):745-50. [Medline].
2. El-Serag HB, Davila JA, Petersen NJ, et al. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med. Nov 18 2003;139(10):817-23. [Medline].
3. Schottenfeld D, Fraumeni JF eds. Cancer Epidemiology and Prevention. 3^rd ed. Oxford University Press; 2006.
4. El-Serag HB, Mason AC. Risk factors for the rising rates of primary liver cancer in the United States. Arch Intern Med. Nov 27 2000;160(21):3227-30. [Medline].
5. American Cancer Society. Statistics for 2008. Available at http://www.cancer.org/docroot/stt/stt_0.asp.
6. Bosch FX, Ribes J, Diaz M, et al. Primary liver cancer: worldwide incidence and trends. Gastroenterology. Nov 2004;127(5 Suppl 1):S5-S16. [Medline].
7. Di Bisceglie AM, Carithers RL Jr, Gores GJ. Hepatocellular carcinoma. Hepatology. Oct 1998;28(4):1161-5. [Medline].
8. Cancer of the Liver and Biliary Tract. In: Adami A, Hunter D, and Trichopoulos D. Textbook of Cancer Epidemiology. Second Edition. Oxford England: Oxford University Press; 2008:308-332.
9. DeVita VT, Lawrence TS, Rosenberg SA, et al. Cancer. In: Principles and Practice of Oncology. 8^th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; May 2008 1.
10. Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med. Jun 26 1997;336(26):1855-9. [Medline].
11. Bugianesi E. Non-alcoholic steatohepatitis and cancer. Clin Liver Dis. Feb 2007;11(1):191-207, x-xi. [Medline].
12. Calle EE, Teras LR, Thun MJ. Obesity and mortality. N Engl J Med. Nov 17 2005;353(20):2197-9. [Medline].
13. Davila JA, Morgan RO, Shaib Y, et al. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut. Apr 2005;54(4):533-9. [Medline].
14. Manos M,and Murphy R. Viral hepatitis registry, Kaiser Permanente Northern California, Oakland, California.Trends in the incidence and etiology of hepatocellular carcinoma in a managed care population :the roles of viral hepatitis and fatty liver disease. Hepatology. 2007;46:400A.
15. Peng SY, Chen WJ, Lai PL, et al. High alpha-fetoprotein level correlates with high stage, early recurrence and poor prognosis of hepatocellular carcinoma: significance of hepatitis virus infection, age, p53 and beta-catenin mutations. Int J Cancer. Oct 20 2004;112(1):44-50. [Medline].
16. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology. Sep 1998;28(3):751-5. [Medline].
17. National Comprehensive Cancer Network. NCCN Hepatobiliary Cancers Clinical Practice Guidelines in Oncology (Version 2.2008). Available at http://www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf.
18. Thomas MB, Zhu AX. Hepatocellular carcinoma: the need for progress. J Clin Oncol. May 1 2005;23(13):2892-9. [Medline].
19. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. Nov 2005;42(5):1208-36. [Medline].
20. Rougier P, Mitry E, Barbare JC, et al. Hepatocellular carcinoma (HCC): an update. Semin Oncol. Apr 2007;34(2 Suppl 1):S12-20. [Medline].
21. Simonetti RG, Liberati A, Angiolini C. Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials. Ann Oncol. 1997;8:117-36. [Medline].
22. Leung TW, Tang AM, Zee B, et al. Factors predicting response and survival in 149 patients with unresectable hepatocellular carcinoma treated by combination cisplatin, interferon-alpha, doxorubicin and 5-fluorouracil chemotherapy. Cancer. Jan 15 2002;94(2):421-7. [Medline].
23. Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol. Apr 20 2006;24(12):1898-903. [Medline].
24. Llovet J, Ricci S, Mazzaferro V, et al. Sorafenib improves survival in advanced hepatocellular carcinoma (HCC): results of a phase III randomized placebo-controlled trial (SHARP trial). J Clin Oncol. 2007;25(suppl):962s(abstract LBA1).
25. Faivre S, Raymond E,Douillard J, et al. Assessment of safety and drug-induced tumor necrosis with sunitinib in patients (pts) with unresectable hepatocellular carcinoma. J Clin Oncol. 2007;25:149s Abstract 3546.
26. Philip PA, Mahoney MR, Allmer C, et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol. Sep 20 2005;23(27):6657-63. [Medline].
27. Thomas M, Dutta A, Brown T, et al. A phase II open-label study of OSI-774 (NSC 718781) in unresectable hepatocellular carcinoma. Proc Am Soc Clin Oncol. 2005;23:4083a.
28. Stuart K. Chemoembolization in the management of liver tumors. Oncologist. 2003;8(5):425-37. [Medline].
29. Stuart K, Stokes K, Jenkins R, et al. Treatment of hepatocellular carcinoma using doxorubicin/ethiodized oil/gelatin powder chemoembolization. Cancer. Dec 1 1993;72(11):3202-9. [Medline].
30. Bruix J, Llovet JM, Castells A, et al. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma: results of a randomized, controlled trial in a single institution. Hepatology. Jun 1998;27(6):1578-83. [Medline].
31. Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. May 18 2002;359(9319):1734-9. [Medline].
32. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. May 2002;35(5):1164-71. [Medline].
33. Poon RT, Fan ST, Lo CM, et al. Improving survival results after resection of hepatocellular carcinoma: a prospective study of 377 patients over 10 years. Ann Surg. Jul 2001;234(1):63-70. [Medline].
34. Takayama T, Makuuchi M, Hirohashi S, et al. Early hepatocellular carcinoma as an entity with a high rate of surgical cure. Hepatology. Nov 1998;28(5):1241-6. [Medline].
35. Hemming AW, Cattral MS, Reed AI, et al. Liver transplantation for hepatocellular carcinoma. Ann Surg. May 2001;233(5):652-9. [Medline].
36. Vauthey JN, Klimstra D, Franceschi D, et al. Factors affecting long-term outcome after hepatic resection for hepatocellular carcinoma. Am J Surg. Jan 1995;169(1):28-34; discussion 34-5. [Medline].
37. Iwatsuki S, Starzl TE, Sheahan DG, et al. Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg. Sep 1991;214(3):221-8; discussion 228-9. [Medline].
38. Fong Y, Sun RL, Jarnagin W, et al. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg. Jun 1999;229(6):790-9; discussion 799-800. [Medline].
39. Curley SA, Izzo F, Ellis LM, et al. Radiofrequency ablation of hepatocellular cancer in 110 patients with cirrhosis. Ann Surg. Sep 2000;232(3):381-91. [Medline].
40. Stuart KE, Anand AJ, Jenkins RL. Hepatocellular carcinoma in the United States. Prognostic features, treatment outcome, and survival. Cancer. Jun 1 1996;77(11):2217-22. [Medline].
41. Collier J, Sherman M. Screening for hepatocellular carcinoma. Hepatology. Jan 1998;27(1):273-8. [Medline].
42. El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology. Nov 2004;127(5 Suppl 1):S27-34. [Medline].
43. Rizell M, Andersson M, Cahlin C, et al. Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer. Int J Clin Oncol. Feb 2008;13(1):66-70. [Medline].

Article Last Updated: Aug 8, 2008