Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related death worldwide.
Most HCCs have characteristic radiological features in imaging including arterial enhancement and delayed washout, although atypical lesions should be confirmed by a second contrast-enhanced study or biopsy13.
Prolonged inflammation owing to viral hepatitis, excessive alcohol intake or non-alcoholic steatohepatitis is the main aetiology for HCC in 90% of cases. The immune microenvironment promotes HCC development by secreting cytokines that favour tumour cell proliferation and suppress anti-tumour adaptive immunity103.
Aetiology
The incidence of liver cancer has rapidly increased and is expected to rise further worldwide1. Hepatocellular carcinoma (HCC) accounts for 90% of all cases. Infection with hepatitis B virus (HBV) is the main risk factor for HCC development in Asia, Mongolia and parts of South America, while hepatitis C virus (HCV) infection constitutes the major aetiology in the United States and Europe. Despite the recent decrease in HCC incidence associated with antiviral therapy of chronic hepatitis C, patients with cirrhosis are at high risk of developing this malignancy. In addition, non-alcoholic steatohepatitis (NASH), associated with metabolic syndrome or diabetes mellitus is becoming the fastest growing aetiology of HCC in the West.
Hepatocellular tumours develop through transformation of normal hepatocytes and are characterized by rapid cell proliferation, invasion and vascularisation. The molecular determinants driving this process remain unclear. However, transcriptomic-based phenotypic classifications of HCC have revealed two major groups: tumours with the pro-tumour signature and tumours with the stem-like phenotype52. The former tumours are characterized by frequent activation of classical cell proliferation pathways including the PI3K-AKT-mTOR and RAS-MAPK cascades and high expression of stem cell markers such as CK19 and EPCAM.
In contrast, tumours with the pro-tumour phenotype are characterised by the accumulation of mutations that promote tumour growth and resistance to chemotherapy53. Several molecular mechanisms contribute to this process, including a dysfunctional DNA damage response and deregulation of cellular processes such as autophagy.
The exact origin of HCC is also under debate, and the involvement of hepatic stem cells, transit amplifying cells or mature hepatocytes has been suggested. The latter are long-lived and retain considerable proliferative potential, which can be activated in response to liver injury. In the chronically inflamed liver, multiple cell types such as hepatic stellate cells, macrophages and different lymphocyte subtypes interact with hepatocytes and can promote or suppress tumourigenesis. These interactions are partly mediated by the secretion of cytokines that favour proliferation, counteract apoptosis or inhibit innate immune responses104. Moreover, hepatocytes can also secrete factors that interfere with senescence-mediated surveillance and promote premalignant phenotype formation105,106.
Diagnosis
HCC can be diagnosed by a combination of tests, including abdominal ultrasound and computed tomography (CT). MRI is the imaging modality of choice for diagnosis of HCC. Liver tissue biopsy can confirm the diagnosis of HCC, but is not a foolproof test and has a low sensitivity when compared to CT [1, 24].
It is important that people who are at risk for hepatocellular carcinoma get regular checkups with their doctors. This is because hepatocellular carcinoma can grow very quickly and spread to other parts of the body, especially the lungs and bones. If hepatocellular carcinoma is found early, it can be cured with surgery or a liver transplant. If it is not caught early, it can be fatal.
Hepatocellular carcinoma is more common in people who have long-term liver disease, like cirrhosis caused by chronic hepatitis B or C infection. It is also more likely to occur in people who drink a lot of alcohol.
The symptoms of hepatocellular carcinoma may include jaundice (yellowing of the skin and eyes) and a feeling of fullness under the ribs on the left side of the abdomen. Other symptoms include fatigue, loss of appetite and weight loss.
Blood tests can show abnormal levels of certain proteins that are released by cancerous liver cells. These include elevated alanine aminotransferase (ALT), bilirubin and alkaline phosphatase. Liver function tests (LFTs) are also often abnormal in people with hepatocellular carcinoma, particularly those with cirrhosis.
Symptoms of advanced hepatocellular carcinoma may include a high fever, fatigue and jaundice. The tumor may also grow rapidly and develop a mass or cyst on the surface of the liver.
Depending on how serious the hepatocellular carcinoma is, it may be treated with chemotherapy drugs or radiation therapy. Chemotherapy drugs kill cancer cells and stop them from growing. Radiation therapy uses a machine that sends beams of radiation directly to the tumor. A doctor can also use a procedure called percutaneous ethanol injection to destroy the tumor. For this, a doctor inserts a thin needle into the artery that supplies blood to your liver. They inject a special medicine called ethanol into the needle, which blocks or destroys the blood flow to the tumor.
Prevention
Hepatocellular carcinoma is a major global health problem and one of the most malignant tumors. It is therefore a prime target for primary cancer prevention, and it lends itself particularly well to interventions targeting viral and other oncogenic causes of the disease.
About 90 to 95 percent of HCC occurs in the setting of persistent hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. These oncogenic viruses are the cause of chronic hepatitis that, over time, leads to liver injury, liver regeneration and fibrosis and cirrhosis, which in turn is associated with increased risk of developing HCC.
Primary prevention can be achieved through vaccination against hepatitis B and screening of blood donations, both of which have been shown to significantly reduce viral hepatitis transmission. A vaccine against hepatitis C is in the final phase of testing, and its introduction into EPIs worldwide could substantially decrease hepatitis C-associated cirrhosis and HCC risk.
In addition to the above, secondary prevention involves the identification and surgical resection or ablation by other means of small pre-symptomatic hepatocellular carcinomas through population screening or case detection programs, which improves the dismal prognosis of patients with symptomatic HCC. However, this intervention is not strictly speaking prevention because it does not involve an attempt to prevent the underlying cause of the tumor. Other minor risk factors for HCC are dietary exposure to aflatoxins in parts of sub-Saharan Africa, China or Taiwan; alcoholic hepatitis; cigarette smoking; and a number of inherited metabolic diseases, the most important of which is hereditary hemochromatosis.
Management
HCC grows slowly in the early stages, and can be treated with surgery to remove the tumor or a liver transplant. This treatment can cure the cancer in some people. But the cancer can recur, so you need to keep seeing your doctor for checkups and to get new treatments.
In the United States, most HCC is found in people with long-term liver disease, such as cirrhosis caused by hepatitis B or hepatitis C infection or by long-term alcohol use. But people without known cause of cirrhosis can also get HCC.
Almost all HCC have characteristic imaging features and are therefore easy to diagnose on routine imaging tests. However, about 10% of tumours lack these features and appear atypical on imaging and require a biopsy or a second contrast-enhanced study.
Once HCC is diagnosed, the next step is to decide on the best treatment. The Barcelona Clinic Liver Cancer staging system links tumor characteristics, underlying liver disease, and performance status to prognosis and management guidelines. A major advance in HCC therapy has been the development of local ablative and trans-arterial therapies including percutaneous ethanol injection (PEI), radiofrequency ablation (RFA) and trans-arterial chemoembolization (TACE).
The surgical removal of HCC is associated with good five-year survival but recurrence is common, especially within two years of surgery. Recurrence correlates with the presence of microscopic vascular invasion. Early recurrence may be related to local invasion or intrahepatic metastasis, while late recurrence is most often associated with de novo tumour formation.
To decrease the risk of recurrence, hepatocellular carcinoma is frequently followed by a combination of surveillance with ultrasonography and serum a fetoprotein and with regular liver biopsy. In high risk patients with hepatitis B virus or in those with hepatitis C liver scarring, biannual surveillance with multiphasic CT or magnetic resonance imaging is recommended.
Liquid biopsy is an important tool to improve the molecular diagnosis of hepatocellular carcinoma. Unlike tissue biopsies, liquid biopsy offers rapid and repeated sampling with minimal invasiveness and allows real-time molecular monitoring. In addition, it can be used to assess response to treatment in hepatocellular carcinoma patients taking mutant EGFR inhibitors.
