Hepatocellular Carcinoma: 5 Things to Know

Managing patients who are at risk for or have been diagnosed with hepatocellular carcinoma (HCC), the most common form of liver cancer, can be daunting. Who should undergo surveillance and how? What is the next step once a liver lesion is identified? What treatment options can be offered?

Here are five things to know about HCC to help answer these difficult questions.

1. The most important risk factor for HCC is cirrhosis.

Cirrhosis precedes HCC in 80%-90% of patients, and one third of all patients with cirrhosis will develop HCC. The incidence of HCC is 1%-8% per year in all patients with cirrhosis (Table 1).

HCC surveillance is recommended for at-risk patient populations every 6 months, in line with the thresholds established by cost-effectiveness models. The rationale behind the frequency of imaging is that HCC has an average 6-month doubling time. For example, a 1-cm tumor not detected on ultrasound imaging will double in size to a 2-cm tumor in 6 months. Ultrasound will be more sensitive for detecting the tumor at this larger size, and the tumor will still be well within the size criteria for curative treatment options. Studies comparing surveillance intervals have also found 6 months to be optimal for improving survival.

Although not as common, HCC can occur without cirrhosis. Hepatitis B infection without cirrhosis is well recognized as leading to HCC. Hepatitis C infection with advanced fibrosis and nonalcoholic steatohepatitis (NASH) have also been associated with noncirrhotic HCC.^[1,2,3]

Table 1. Incidence of HCC by Population^{[1,2,3,4,5,6]}

2. Fatty liver is a major factor contributing to the rise in HCC incidence.

Large prospective studies in the United States and Europe have established the relationship between NASH and HCC.Among the US population, the prevalence of nonalcoholic fatty liver disease (NAFLD) is 25% and NASH is 3%, with 40% of all patients with NASH progressing to advanced stages of fibrosis.

Although there are reports of liver cancer developing in the background of NASH without cirrhosis, the incidence is low, occurring at a rate of only 0.1% per year (Table 1).^[4,5,6] However, with NAFLD affecting one third of the US population, the magnitude of noncirrhotic NASH contributing to HCC is worth noting.

Genetic factors, such as the presence of PNPLA3, also are associated with a high susceptibility to NASH and thus a risk for HCC.

3. Treating chronic hepatitis infection reduces the risk for HCC but does not eliminate it.

Curing chronic hepatitis C infection is associated with a 71% risk reduction of incident HCC. This is by far the most effective way to decrease the risk for future liver cancer, especially in those with advanced fibrosis.

Patients with hepatitis C infection who have advanced liver fibrosis (stage F3) or cirrhosis should receive surveillance imaging before treatment is initiated with direct-acting antiviral agents (DAAs), and surveillance should be continued thereafter.

The presence of active HCC is associated with a slightly lower sustained virologic response to DAA therapy. For this reason, patients eligible for liver resection or ablation, and in some cases transplant, should defer DAA therapy until after such treatment is completed. Treatment with DAAs in patients with more advanced HCC should be weighed against tumor burden, degree of liver dysfunction, life expectancy, and patient preferences. DAAs are not associated with tumor recurrence after complete response to HCC treatment, but therapy for hepatitis C virus infection can be deferred 4-6 months to confirm complete control of the tumor.

Patients with a complete response to HCC therapy who are treated with DAAs require HCC surveillance indefinitely with CT scan or MRI every 3-6 months owing to a continued risk for HCC recurrence.

4. A liver biopsy is not necessary for the diagnosis of liver cancer.

When a liver lesion is identified, cross-sectional dynamic phase imaging (CT scan or MRI) is performed using the Liver Imaging Reporting and Data System, which determines the likelihood of HCC by accounting for its typical features (eg, size, arterial enhancement, washout, enhancing capsule, growth). Hepatic protocol with quadruple-phase imaging (precontrast phase, arterial phase, portal venous phase, and delayed phase) is also recommended.

The choice of CT scan or MRI often depends on the technology available and institutional preference; however, a meta-analysis concluded that MRI is more sensitive than CT scan (80% vs 68%). Hepatobiliary-specific gadolinium (Gd-BOPTA and Gd-EOB-DTPA) is even more sensitive for small lesions, but timing in phase may be different than standard gadolinium.For patients with renal dysfunction or an allergy to CT scan contrast material, contrast-enhanced ultrasound is an option; the "contrast" agent is gas-filled microbubbles. Contrast-enhanced ultrasound can also be used to distinguish nontumor versus tumor thrombus.

Alpha-fetoprotein (AFP) is commonly used to help diagnose HCC. In addition to AFP, new tumor markers (AFP binding to Lens culinaris agglutinin, des-gamma-carboxyprothrombin) are available, with several emerging options in the pipeline.^[7,8,9] Together, these biomarkers have an improved sensitivity in surveillance and diagnosis of HCC and may have a role in predicting response to treatment and prognosis.

Liver biopsy is now reserved for indeterminate lesions but may have a more robust role with the development of molecular therapies and precision medicine.

5. Curative options are available if HCC is identified at an early stage.

Curative therapies for HCC include resection, ablation, and liver transplantation.

Surgical resection is the treatment of choice for patients with early-stage cancer and preserved liver function, with a 5-year survival rate of approximately 70%. Recurrence is associated with the presence of microscopic vascular invasion. The risk and benefit of surgical resection should be weighed against local regional ablative therapies.

Ablation is an option for early-stage tumors not amenable to surgery. Radiofrequency ablation has replaced percutaneous ethanol ablation as the targeted therapy of choice. The best results with radiofrequency ablation were seen in newly diagnosed cancers with lesions < 2 cm, resulting in a 5-year survival rate of 47%-68%. Microwave coagulation therapy is a newer ablative approach that induces coagulate necrosis in tumors and may be more suitable for tumors in unfavorable locations or those > 3 cm in diameter.

Patients with HCC who have cirrhosis but do not have portal hypertension may be eligible for liver resection. However, if portal hypertension is present, transplant is the best curative option. In the United States, 20%-30% of all transplants are for HCC. After liver transplant, the 1-year survival rate is 94%, and the 3-year survival rate is 80%; the recurrence rate of HCC is 10%-15%.

Patients with HCC who are not eligible for curative options should be considered for palliative therapy, including transarterial chemoembolization and transarterial radioembolization, stereotactic body radiation therapy, or systemic chemotherapy. Palliative therapy may also be used for patients awaiting transplantation.

Until recently, sorafenib, an oral multikinase inhibitor, was the only approved systemic therapy for HCC. Now several systemic chemotherapy options are available for unresectable HCC in patients with otherwise well-preserved liver function (Table 2).^{[10,11,12,13,14,15,16,17]}

Table 2. Systemic Chemotherapy Options for HCC^{[10,11,12,13,14,15,16,17]}

Sheila L. Eswaran, MD, MS, is an associate professor in the hepatology section at Rush University Medical Center in Chicago. Her clinical and research interests are liver cancer and alcoholic hepatitis. She is co-chair of the American Liver Foundation Great Lakes Division Medical Advisory Committee.

Nancy S. Reau, MD, is chief of the hepatology section at Rush University Medical Center in Chicago, and a regular contributor to Medscape. She serves as editor of Clinical Liver Disease, a multimedia review journal, and recently as a member of HCVGuidelines.org, a web-based resource from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America, as well as educational chair for the AASLD hepatitis C special interest group. She continues to have an active role in the hepatology interest group of the World Gastroenterology Organisation and the American Liver Foundation at the regional and national levels.

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