What is hepatocellular carcinoma?

Hepatocellular Carcinoma Overview

Hepatocellular carcinoma (HCC) is an epithelial liver tumor whose cells share characteristics with normal hepatocytes, representing the most common primary liver malignancy in adults and the third leading cause of cancer-related death worldwide. 1

Epidemiology and Global Burden

• HCC ranks as the fifth most common cancer globally and demonstrates the highest average annual percent increase among the top 15 cancers by incidence in the United States. 1
• The crude incidence in the European Union is 8.29 per 100,000, while high-prevalence regions such as Asia and sub-Saharan Africa report rates as high as 120 cases per 100,000. 1
• HCC occurs 4-8 times more commonly in men than women, with median age at diagnosis between 50-60 years in Western countries. 1
• In Africa and Asia, diagnosis occurs substantially younger, typically in the fourth and fifth decades of life. 1

Pathogenesis and Risk Factors

Underlying Liver Disease

• Advanced fibrosis and cirrhosis—irrespective of etiology—represent the ideal substrate for HCC development, with approximately 80-90% of cases occurring in cirrhotic livers. 1
• Only less than 10% of HCC cases occur in normal liver parenchyma. 1

Major Etiologic Factors

• Chronic hepatitis B virus (HBV) infection in the setting of cirrhosis increases HCC risk 1000-fold. 1
• Chronic hepatitis C virus (HCV) infection leads to cirrhosis in approximately 30% of chronically infected individuals, with 1-2% per year developing HCC once cirrhosis is established. 1
• The geographic distribution of HCC prevalence mirrors that of HBV and HCV infection patterns worldwide. 1
• Alcohol abuse in the setting of chronic HCV infection doubles the HCC risk compared with HCV infection alone. 1
• Additional risk factors include iron overload (hemochromatosis), metabolic dysfunction-associated steatotic liver disease (MASLD), and alcoholic liver disease. 1, 2

Epidemiologic Risk Factors

• Male gender, advanced age, obesity, and diabetes mellitus all contribute to increased HCC risk. 1
• HBV co-infection with HCV further amplifies HCC risk beyond either infection alone. 1

Cellular Origin and Molecular Features

• Uncertainty remains regarding the cell of origin, which may be either a liver stem cell or a mature hepatocyte. 1
• HCC expressing biliary-type cytokeratins (CK7 and/or CK19) may indicate progenitor cell origin and carries a poor prognosis. 1
• A dysplastic lesion can evolve into malignant tumor through a genetic progression model similar to other cancers. 1
• HCC may also evolve from recently defined subclasses of hepatic adenomas. 1

Clinical Presentation and Natural History

• Tumors are multifocal within the liver in 75% of cases at diagnosis. 1
• More than 70% of HCC patients present with advanced disease that precludes curative treatment options such as resection, ablation, or transplantation. 1
• Average survival after symptom onset is less than 1 year without treatment, reflecting the highly malignant nature of this cancer. 1
• Most patients have underlying cirrhosis and hepatic dysfunction—representing "one patient with two diseases"—which significantly complicates management and clinical trial eligibility. 1

Special Variants

• Fibrolamellar HCC occurs in young patients without traditional risk factors, demonstrates slow growth, and carries a significantly better prognosis. 1
• These variants are typically excluded from HCC therapeutic trials due to their distinct natural history. 1
• The fibrolamellar variant is not associated with cirrhosis. 1

Prevention Potential

• Unlike most cancers, HCC is largely preventable because it occurs in the context of identifiable risk factors. 1
• Universal HBV vaccination at birth has already demonstrated decreased HCC rates in Taiwan and forms the foundation of prevention strategies. 1
• There remains an unmet need for implementing comprehensive programs addressing prevention, vaccination, early diagnosis, and treatment of underlying liver disease. 1

Key Clinical Pitfalls

• Any deterioration in liver function in a patient with known cirrhosis of any etiology should raise immediate suspicion for HCC. 1
• The incubation period between HCV infection onset and HCC appearance spans 2-4 decades, explaining the current epidemic in developed countries following 1960s-1970s HCV transmission. 1
• Even with successful resection or ablation, recurrence is common because the underlying conditions (cirrhosis, viral hepatitis) that led to initial HCC typically persist. 1