Primary Hepatic Carcinoma

Practice Essentials

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 of cirrhosis or risk factors for it. The extent of hepatic dysfunction limits treatment options, and as many patients die of liver failure as from tumor progression.

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Hepatic carcinoma, primary. Large multifocal hepatocellular carcinoma (HCC) in an 80-year-old man without cirrhosis.

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.

For patient education resources, see the Hepatitis Center and Liver, Gallbladder, and Pancreas Center, as well as Cirrhosis, Hepatitis B, Hepatitis C, and Liver Transplant.

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Pathophysiology

Tumors are multifocal within the liver in 75% of cases. Late in the disease, metastases may develop in the lung, portal vein, periportal nodes, bone, or brain (see images below).

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Hepatic carcinoma, primary. Dilated collateral superficial abdominal veins in a 67-year-old man with cirrhosis, hepatocellular carcinoma (HCC), and po....

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Hepatic carcinoma, primary. Unusual location of a bone metastasis from hepatocellular carcinoma (HCC).

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Etiology

Cirrhosis

In general, cirrhosis of any etiology is the major risk factor for hepatocellular carcinoma.^{[1, 2]}  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.^[3]

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 infection

The global incidence of chronic hepatitis B virus (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.^[4]  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 will decrease.

Hepatitis C virus infection

Hepatitis C virus (HCV) infection is a global pandemic affecting 170 million persons. HCV infection results in a higher rate of chronic infection compared with HBV infection (approximately 80% of infected subjects).

HCV infection 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.^[5]  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.

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.

Metabolic factors

Obesity and diabetes have been implicated as risk factors for hepatocellular carcinoma, most likely through the development of nonalcoholic steatohepatitis (NASH).^{[6, 7, 8, 9]}  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.^[10]

Rare associations

These include the following:

• Primary biliary cirrhosis
• Androgenic steroids
• Primary sclerosing cholangitis
• Alpha1-antitrypsin deficiency
• Thorotrast radioactive contrast
• Oral contraceptives
• Porphyria cutanea tarda. 

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Epidemiology

Frequency

United States

The incidence of HCC has more than tripled since 1980; from 2005 to 2014, the rate increased by about 3% per year. For 2018, the American Cancer Society estimates that 42,220 new cases of hepatocellular carcinoma and intrahepatic bile duct cancers will be diagnosed and 30,200 deaths will occur.^[11]

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.^[12]

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 is about 3 times more common in men than in women in the United States.^[11]  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.^[13]

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Prognosis

Overall prognosis for survival is poor, with a 5-year relative survival rate of 18%. In patients diagnosed with a localized stage of disease, the 5-year survival is 31%.^[11]  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.

The influence of diabetes, obesity, and glycemic control continues to be evaluated in studies of the etiology and outcomes of HCC. For example, in a study of patients who had undergone curative resection for solitary HCV-related HCC, the tumor-free survival rate at 3 years was more than twice as high in patients in patients who had a normal hemoglobin A1c than in those whose hemoglobin A1c was 6.5% or higher (66% versus 27%).^[14]

Complications from HCC are those of hepatic failure; death occurs from cachexia, variceal bleeding, or (rarely) tumor rupture and bleeding into the peritoneum. Signs and symptoms of hepatic failure may signify tumor recurrence and/or progression.

Various studies have reported extrahepatic metastasis in up to 30–50% of cases of HCC, with lungs the commonest site, followed by lymph nodes and bones. Unusual extrahepatic metastatic sites include the following^[15] :

• Adrenal glands
• Peritoneum
• Diaphragm
• Soft tissues
• Brain
• Skin
• Oral cavity

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History

Patients generally present with signs and symptoms of advancing cirrhosis, as follows:

• 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) 

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Physical Examination

Physical  examination findings include:

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

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Laboratory Studies

Expect the following studies to show results consistent with cirrhosis:

• Total bilirubin
• Aspartate aminotransferase (AST)
• Alkaline phosphatase
• Albumin
• Prothrombin time

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). 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.^[16]

Des-gamma-carboxy prothrombin (DCP) has been studied as a biomarker for early diagnosis of hepatocellular carcinoma. Lok et al found that the sensitivity and specificity of DCP at the time of diagnosis of hepatocellular carcinoma was 74% and 86%, respectively, at a cutoff of 40 mAU/mL and 43% and 100%, respectively, at a cutoff of 150 mAU/mL. Twelve months before diagnosis, the sensitivity and specificity at the 40 mAU/mL cutoff was 43% and 94%.^[17] Combining DCP with AFP increased the sensitivity to 91% but lowered the specificity to 74%. Lok et al concluded that DCP is not optimal for detection of early hepatocellular carcinoma.

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Imaging Studies

Obtain liver imaging using ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI). See the image below. 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.

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Hepatic carcinoma, primary. Noncontrast CT scans at 1 day and 3 months following chemoembolization with doxorubicin/Ethiodol Gelfoam.

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 image below).

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Hepatic carcinoma, primary. Plain radiograph immediately following chemoembolization, demonstrating catheter placement and Ethiodol enhancement of tum....

Bone scanning and head CT scanning are of low yield in the absence of specific symptoms.

Positron emission tomography (PET) scanning has been evaluated in the experimental setting, but to date its role is uncertain. Routine use of PET scanning for diagnosis or staging of hepatocellular carcinoma is not recommended.

For more information, see Hepatocellular Carcinoma Imaging.

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Liver Biopsy

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 in 1000), while others show no difference. Regardless, potential risks and complications should be considered before performing a biopsy.

Biopsy may be omitted in a  patients with a growing mass in a cirrhotic liver (>2 cm) visualized with 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. In addition, btaining a biopsy may be unnecessary in patients who will be undergoing resection regardless of the diagnosis.

Biopsy is generally performed 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 who have severe thrombocytopenia (< 50,000/μL). 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.

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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.

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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 have unresectable disease and prognosis actually depends more on the state of the liver than on 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.^[5]

Currently, perhaps the most widely accepted and reproducible of such staging systems are the Barcelona Clinic Liver Cancer (BCLC) system^{[7, 18]} and the Cancer of the Liver Italian Program (CLIP) scoring system. CLIP assigns a cumulative prognostic score ranging from 0-6 based on Child-Pugh class, tumor morphology, alpha-fetoprotein level, and portal vein thrombosis, which can predict median survival time.^[19] The BCLC system includes a treatment algorithm that helps with individual patient decisions.^{[3, 20]} Both systems have strong proponents, and each has been externally validated in multiple populations.^{[11, 12, 13, 1]}

Below is a summary of 3 staging systems.

TNM staging criteria for hepatocellular carcinoma

See the list below:

• 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 - No nodal involvement
• N1 - Regional nodal involvement
• M0 - No distant metastasis
• M1 - Metastasis presence beyond the liver

Stage grouping:

See the list below:

• 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

A score of 0-2 is assigned for each of the 4 features listed below; a cumulative score ranging from 0-6 is the CLIP score.

Child-Pugh class:

• Class A = 0
• Class B = 1
• Class 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.

BCLC algorithm

See the algorithm below.

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The Barcelona Clinic Liver Cancer (BCLC) staging system for hepatocellular carcinoma. Image reproduced with permission reproduced with permission of t....

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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.^[21]

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 (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.

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Approach Considerations

Treatment options for hepatocellular carcinoma depend on the following^{[22, 23, 24]} :

• Size, number, and location of tumors
• Presence or absence of cirrhosis
• Operative risk based on extent of cirrhosis and comorbid diseases
• Overall performance status
• Portal vein patency
• Presence or absence of metastatic disease

Before instituting definitive therapy, it is best to treat the complications of cirrhosis, as follows:

• Sodium restriciton, diuretics, and paracentesis for ascites
• Lactulose for encephalopathy
• Ursodiol for pruritus
• Sclerosis or banding for variceal bleeding
• Antibiotics for spontaneous bacterial peritonitis

Surgical resection and liver transplantation provide 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.^[25]  

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.

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Medical Care

Systemic chemotherapy

Systemic chemotherapy remains the mainstay of therapy for patients with advanced hepatocellular carcinoma who are not candidates for surgical resection, liver transplantation, or localized tumor ablation. 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.^{[26, 23]} 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. Cisplatin-based combination regimens, such as gemcitabine and oxaliplatin, have shown improved response rates around 20%, but to date, no survival advantage as compared with 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.^[27]

Antiangiogenic therapy 

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.  However, the combination of bevacizumab with gemcitabine and oxaliplatin produced a 20% response rate, and stable disease in an additional 27% of patients.^[28]  

Sorafenib, a multitargeted oral kinase inhibitor, has been shown in a phase III trial to prolong survival in patients with hepatocellular carcinoma.^[29] This agent, which targets various pathways, including those encoded by VEGFR, PDGFR, KIT, FLT-3, and RET, was compared with 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 months in the placebo group. Currently, this is the only FDA-approved antineoplastic for hepatocellular carcinoma. The revised National Comprehensive Cancer Network (NCCN) guidelines for hepatocellular carcinoma recommend sorafenib as a treatment option at several points in the treatment algorithm.^[22]

The benefit of sorafenib was also demonstrated in a study by Abou-Alfa et al, which showed a longer overall and progression-free survival with the addition of sorafenib to doxorubicin. The same study underlines the lack of efficacy of doxorubicin alone.^[30] Still unanswered is the question of whether doxorubicin adds any benefit to treatment with sorafenib by itself.

Sunitinib is another multitargeted tyrosine kinase inhibitor with reported activity in hepatocellular carcinoma.^[31] Erlotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has also shown some activity against hepatocellular carcinoma when used alone or in combination with bevacizumab.^{[32, 33]} One report has suggested that the mTOR inhibitor sirolimus may have benefit in the treatment of both cholangiocellular carcinoma and hepatocellular carcinoma.^[33]

Immunotherapy

Immune checkpoint inhibitors have been proven to lead to durable tumor shrinkage in a subset of patients that has translated into significant overall survival advantages over standard therapy in several cancer types. Interference with the CTLA-4-CD80/86 and PD-1/PD-L1 axis has shown promise in patients with hepatocellular carcinoma and many clinical trials using this approach have been reported or are currently under way.^[34]

On September 22, 2017, the US Food and Drug Administration granted accelerated approval to the anti–programmed death 1 monoclonal antibody nivolumab (Opdivo) for the treatment of hepatocellular carcinoma in patients who have been previously treated with sorafenib.  Approval was based on a 154-patient subgroup of CHECKMATE-040, a multicenter, open-label trial conducted in patients with hepatocellular carcinoma and Child-Pugh A cirrhosis who progressed on or were intolerant to sorafenib. Patients received nivolumab 3 mg/kg by intravenous infusion every 2 weeks. The confirmed overall response rate was 14.3% (95% CI: 9.2, 20.8), with 3 complete responses and 19 partial responses. Response duration ranged from 3.2 to 38.2+ months; 91% of responders had responses lasting 6 months or longer and 55% had responses lasting 12 months or longer.^[35]

Common adverse reactions occurring in greater than 20% of patients in nivolumab clinical trials include fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, and pyrexia.^[35]

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Surgical Care

Partial hepatectomy

The videos below demonstrate a right hepatectomy.

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Right hepatectomy. Part 1: Dissection of right portal vein. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Leslie H. Blumgart, MD. (From Blumgart LH. Video Atlas: Liver, Biliary & Pancreatic Surgery. Philadelphia, PA: Saunders; 2010.)

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Right hepatectomy. Part 2: Devascularization of right liver. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Leslie H. Blumgart, MD. (From Blumgart LH. Video Atlas: Liver, Biliary & Pancreatic Surgery. Philadelphia, PA: Saunders; 2010.)

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Right hepatectomy. Part 3: Suturing and dividing. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Leslie H. Blumgart, MD. (From Blumgart LH. Video Atlas: Liver, Biliary & Pancreatic Surgery. Philadelphia, PA: Saunders; 2010.)

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.^{[36, 37]} 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.

Local liver factors rather than tumor-associated characteristics may be instrumental in tumor recurrences following surgical resection. For instance, one study found that the level of HBV-DNA in the liver tissue surrounding the tumor was a strong determinant of recurrence, rather than the amount of HBV-DNA in the resected tumor itself.^[38]

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.^{[39, 40, 41, 42]}

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.

Locally ablative therapy

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. This has generally been supplanted by other local modalities.

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.^{[43, 44]}

Multimodel management by combining RFA with different techniques, including percutaneous ethanol injection, transarterial chemo-embolization, targeted molecular therapy, nanoparticle-mediated therapy, and immunotherapy have been investigated. The combination strategy  has improved outcomes in comparison to RFA alone.^[45]

Cryoablation, using a liquid nitrogen–filled probe, can achieve similar results to RFA and is also used for tumors smaller than approximately 5 cm. The degree of collateral damage to uninvolved liver tissue or other organs may be more easily appreciated, so this technique is more useful for lesions near the surface of the liver, the gallbladder, or large blood vessels.

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.

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.^[46]

Some centers are adding RFA to chemoembolization in the hope that the combined treatments would improve outcome by adding thermal ablation to arterial ischemia. A randomized controlled trial by Morimoto et al demonstrated an improved local control without a definite improvement in overall survival.^[47] However, the study did not include a chemoembolization-alone arm, so it remains unclear whether both procedures together are necessary for local control.

Embolizing agents such as cellulose, microspheres,^[48] lipoidal, and gelatin foam particles are used to deliver intra-arterial chemotherapy (mitomycin, doxorubicin, cisplatin) to the tumor via the hepatic artery. A relatively new technology using drug-eluting beads may offer similar efficacy with less toxicity.

Morbidity from this procedure is greatly dependent on the extent of cirrhosis. In general, patients with portal vein thrombosis, significant encephalopathy, or biliary obstruction are not candidates for chemoembolization.^[49]

Response rates of 60-80% are seen. In addition, 2 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.^{[50, 51, 52]}

Radioembolization (or selective internal radiotherapy) uses 32-μm glass microspheres to carry yttrium-90 intra-arterially into the capillary beds of the tumor. This technique can cause excellent necrosis and tumor responses. Unlike chemoembolization, which uses larger particles, arterial embolization and ischemia are not necessary for the therapeutic effect, meaning this procedure may be performed for patients with portal vein thrombosis.^{[53, 54]}

• References

Consultations

Consultation with the following specialists is recommended:

• Hepatobiliary surgeon
• Oncologist
• Interventional radiologist
• Interventional gastroenterologist

• References

Diet

Patients should avoid alcohol and other hepatic toxins because prognosis is related to worsening cirrhosis and tumor stage. The consumption of fish and fish-associated fatty acids is associated in a dose-dependent fashion with a lower risk of the development of HCC, regardless of hepatitis status.^[55]

• References

Prevention

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. Assuming that present HBV vaccination trends continue, between 2020 and 2050, the number of new HBV infections is estimated to drop by 70%.^[56]  

Other primary prevention approaches include decreasing harmful use of alcohol, implementation of safe injection and transfusion practices, improved diagnoses of chronic infections, and increased treatment for HBV and HCV including increased accessibility and affordability of the highly effective HCV antiviral medication.^{[56, 57]}

The Centers for Disease Control and Prevention (CDC) recommends one-time HCV testing for everyone born from 1945 to 1965 because this cohort  accounts for about three-fourths of HCV-infected individuals in the US. Preventive measures for HBV and HCV infection recommended by the CDC include screening of donated blood, organs, and tissues; adherence to infection control practices during medical and dental procedures; needle-exchange programs for injection drug users; and practicing safe sex. ^[58]

• References

Long-Term Monitoring

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.

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Guidelines Summary

Guidelines Contributor:  Elwyn C Cabebe, MD Physician Partner, Valley Medical Oncology Consultants; Medical Director of Oncology, Clinical Liason Physician, Cancer Care Committee, Good Samaritan Hospital

Guidelines for the screening, surveillance, and diagnosis of hepatocellular carcinoma (HCC) have been issued by the following organizations:

• American Association for the Study of Liver Diseases (AASLD)
• National Comprehensive Cancer Network (NCCN)
• American College of Gastroenterology (ACG)
• European Association for the Study of the Liver (EASL)–European Organisation for Research and Treatment of Cancer (EORTC)
• European Society of Medical Oncology (ESMO)–European Society of Disease Oncology (ESDO)

Screening and Surveillance

In their 2010 guidelines for the management of HCC, the American Association for the Study of Liver Diseases (AASLD) recommends HCC screening and surveillance for the following high-risk groups^[59] :

• Asian male hepatitis B carriers over age 40
• Asian female hepatitis B carriers over age 50
• Hepatitis B carriers with a family history of HCC
• Africans and African Americans with hepatitis B
• Cirrhotic hepatitis B carriers
• Individuals with hepatitis C cirrhosis
• Individuals with stage 4 primary biliary cirrhosis
• Individuals with genetic hemochromatosis and cirrhosis
• Individuals with alpha 1-antitypsin deficiency and cirrhosis
• Individuals with cirrhosis from other etiologies

In addition, individuals awaiting liver transplantation should be screened because HCC may progress beyond the listing criteria for liver transplantation and those with HCC are given increased priority on the transplant waiting list.^[59]

In accordance with the AASLD guidelines, HCC screening should be performed in a setting in which screening tests and recall procedures have been standardized and quality control procedures are in place. Surveillance should be performed at 6-month intervals, using ultrasonography.{ref70

The NCCN guidelines identify similar high-risk groups but recommend screening with alfa-fetoprotein (AFP) testing and ultrasonography every 6 to 12 months.^[22]

The AASLD recommendations for follow-up of abnormal screening results include the following^[59] :

• For nodules identified on ultrasound that are < 1 cm, ultrasound should be repeated at intervals of 3-6 months; if no growth is observed over a period of up to 2 years, revert to routine surveillance
• For nodules >1 cm on a cirrhotic liver, follow-up with either four-phase multidetector CT scan or dynamic contrast enhanced MRI. If the appearances are typical of HCC (ie, hypervascular in the arterial phase with washout in the portal venous or delayed phase), the lesion should be treated as HCC; if the findings are not characteristic or the vascular profile is not typical, a second contrast enhanced study with the other imaging modality should be performed, or the lesion should be biopsied
• Biopsies of small lesions should be evaluated by expert pathologists; tissue that is not clearly HCC should be stained with all the available markers (including CD34, CK7, glypican 3, HSP-70, and glutamine synthetase) to improve diagnostic accuracy
• If the biopsy is negative, the lesion should be followed by imaging at 3- to 6-month intervals until the nodule disappears, enlarges, or develops features characteristics of HCC
• If the lesion enlarges but remains atypical for HCC, the biopsy should be repeated

The 2014 American College of Gastroenterology (ACG) guidelines for the diagnosis and management of focal liver lesions (FLLs) include the following recommendations^[60] :

• Patients with cirrhosis in whom an ultrasound shows a lesion of >1 cm should undergo an MRI or triple-phase CT scan
• Patients with chronic liver disease who are at a very high risk for HCC and who present with a solid FLL must be considered to have HCC until proved otherwise
• HCC can be diagnosed with CT or MRI if the typical characteristics are present
• If an FLL in a patient with cirrhosis does not have typical characteristics of HCC, then a biopsy should be performed

NCCN guidelines recommend that diagnosis be made with one or more of the following imaging modalities if clinical suspicion is high^[22] :

• Four-phase helical CT
• Four-phase dynamic contrast-enhanced MRI
• Contrast-enhanced ultrasound

The NCCN does not consider PET/CT appropriate for diagnosis.

NCCN surveillance recommendations are as follows^[22] :

• Lesions ≤1 cm should be reevaluated every 3 to 6 months; if the lesion remains stable, after 2 years the surveillance schedule can return to every 6 to 12 months
• Liver nodules >1 cm in size should first be evaluated with at least three-phase contrast-enhanced CT or MRI (including late arterial and portal venous phases)
• Additional imaging depends on the pattern of classic enhancement observed on CT/MRI: a finding of two classic enhancements (arterial hyperenhancement with washout in the venous phase) is diagnostic of HCC, whereas if fewer than two enhancement patterns are seen, a second imaging (the other of CT or MRI) is recommended; if two enhancements are seen with additional imaging, the diagnosis of HCC is confirmed
• For nodules that do not demonstrate both hyperenhancement and washout, core biopsy (preferred) or fine-needle aspiration (FNA) is recommended; alternatively, patients with nodules 1-2 cm in size can be followed with repeat imaging in 3 mo

The AASLD considers a single imaging study sufficient to diagnosis HCC in patients with cirrhosis and liver nodules between 1 and 2 cm.^[59]

Joint guidelines published in 2012 by the European Association for the Study of the Liver (EASL) and the European Organisation for Research and Treatment of Cancer (EORTC) are generally in agreement with NCCN and AASLD guidelines on noninvasive diagnosis using one imaging technique (four-phase CT or dynamic contrast-enhanced MRI).^[61]

The European Society of Medical Oncology (ESMO)–European Society of Disease Oncology (ESDO) 2012 joint guidelines for diagnosis and treatment of HCC require biopsy for diagnosis except in the following patients with cirrhosis^[61] :

• Individual is not a candidate for any therapy due to serious comorbidity
• Individual is on the waiting list for a liver transplantation
• Individual is candidate for resection

Staging

The tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control/ (AJCC/UICC) is useful only in patients who undergo surgical resection, which is a small minority of patients. Only the NCCN guidelines follow TNM for staging.^[22]

Since most patients have unresectable disease and prognosis depends more on the state of the liver than on the size of the tumor, the AASLD, EASL-EORTC, and ESMO-ESDO guidelines recommend the Barcelona Clinic Liver Cancer (BCLC) system for prognostic prediction and treatment stratification.^{[59, 60, 61, 62]}

The BCLC staging system attempts to overcome the limitations of previous staging systems by identifying prognostic stages (0 and A through D) based on five variables^[63] :

• Tumor stage
• Functional status of the liver
• Physical status
• Cancer-related symptoms

The BCLC staging system also links each HCC stage to appropriate treatment modalities as follows:

• Patients with early-stage HCC (stage 0 and A) may benefit from curative therapies (ie, liver transplantation, surgical resection, radiofrequency ablation).
• Patients with intermediate-stage(stage B) or advanced-stage (stage C) disease may benefit from palliative treatments (ie, transcatheter arterial chemoembolization and sorafenib)
• Patients with end-stage disease (stage D) are offered supportive care and palliation

Treatment

The guidelines agree that resection is the treatment of choice for solitary tumors in non-cirrhotic patients or cirrhotic patients with well-preserved liver function. Pre- or post-resection adjuvant therapy is not recommended.

The guidelines further concur that liver transplantation is the best available curative option for patients with early-stage non-resectable HCC who meet the Milan criteria (single tumors ≤5 cm in diameter or no more than three nodules ≤3 cm in diameter in patients with multiple tumors). Ablation should be considered as definitive treatment for patients with stage 0-A tumors who are not candidates for resection or transplantation.^{[59, 22, 61, 62]}  NCCN and AASLD guidelines also recommend ablation as a possible bridge therapy for patients awaiting transplantation.^{[59, 22]}

The AASLD recommends transarterial chemoembolization as first-line noncurative therapy for advanced disease. Sorafenib is recommended for patients who have preserved liver function and cannot benefit from surgery, transplantation, ablation, or transarterial chemoembolization. Yttrium-90 radioembolization is not recommended outside of clinical trials. Systemic or selective intra-arterial chemotherapy is not recommended.^[59]

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Medication Summary

Systemic chemotherapy remains the mainstay of therapy for patients with advanced hepatocellular carcinoma who are not candidates for surgical resection, liver transplantation, or localized tumor ablation. Unfortunately, hepatocellular carcinoma is a relatively chemotherapy-resistant tumor. Antiangiogenic and immunotherapy agents have yielded promising results.

• References

Sorafenib (Nexavar)

• Dosing, Interactions, etc.

Clinical Context:  First oral multikinase inhibitor that targets serine/threonine and tyrosine receptor kinases in both the tumor cell and the tumor vasculature. Targets kinases involved in tumor cell proliferation and angiogenesis, thereby decreasing tumor cell proliferation. These kinases included RAF kinase, VEGFR-2, VEGFR-3, PDGFR-beta, KIT, and FLT-3. Indicated for unresectable hepatocellular carcinoma.

• References

Sunitinib (Sutent)

• Dosing, Interactions, etc.

Clinical Context:  Mulitkinase inhibitor that targets several tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression. Inhibits platelet-derived growth factor receptors (ie, PDGFR-alpha, PDGFR-beta), vascular endothelial growth factor receptors (ie, VEGFR1, VEGFR2, VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor receptor type 1 (CSF-1R), and the glial cell-line–derived neurotrophic factor receptor (RET).

• References

Erlotinib (Tarceva)

• Dosing, Interactions, etc.

Clinical Context:  Pharmacologically classified as a human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. EGFR is expressed on the cell surface of normal cells and cancer cells.

• References

Class Summary

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

• References

Sirolimus (Rapamune)

• Dosing, Interactions, etc.

Clinical Context:  Interferes with signal transduction pathways.

• References

Class Summary

Agents that inhibit signal transduction pathways may be of benefit.

• References

Nivolumab (Opdivo)

• Dosing, Interactions, etc.

Clinical Context:  Monoclonal antibody to programmed cell death-1 protein (PD-1); blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2

• References