Liver cancer, also known as hepatic cancer, is a cancer that originates in the liver. Liver tumors are discovered on medical imaging equipment (often by accident) or present themselves symptomatically as an abdominal mass, abdominal pain, yellow skin, nausea or liver dysfunction.
The leading cause of liver cancer is cirrhosis due to either hepatitis B, hepatitis C, or alcohol. In 2013, 300,000 deaths from liver cancer were due to hepatitis B, 343,000 to hepatitis C and 92,000 to alcohol. Liver cancers are not the same as liver metastases, which start in another part of the body and spread to the liver. Liver cancers are formed from either the liver itself or from structures within the liver, including blood vessels or the bile duct.
Primary liver cancer is globally the sixth most frequent cancer, and the second leading cause of cancer death. In 2012 it occurred in 782,000 people and resulted in 746,000 deaths. Higher rates of liver cancer occur where hepatitis B and C are common, including East-Asia and sub-Saharan Africa. Five year survival rates are 17% in the United States. Hepatic is from the Greek hêpar, meaning “liver”.
The most frequent liver cancer, accounting for approximately 75% of all primary liver cancers, is hepatocellular carcinoma (HCC) (also named hepatoma, which is a misnomer because adenomas are usually benign). HCC is a cancer formed by liver cells, known as hepatocytes, that become malignant. Another type of cancer formed by liver cells is hepatoblastoma, which is specifically formed by immature liver cells. It is a rare malignant tumor that primarily develops in children, and accounts for approximately 1% of all cancers in children and 79% of all primary liver cancers under the age of 15. Most hepatoblastomas form in the right lobe.
Liver cancer can also form from other structures within the liver such as the bile duct, blood vessels and immune cells. Cancer of the bile duct (cholangiocarcinoma and cholangiocellular cystadenocarcinoma) account for approximately 6% of primary liver cancers. There is also a variant type of HCC that consists of both HCC and cholangiocarcinoma. Tumors of the blood vessels (angiosarcoma and hemangioendothelioma, embryonal sarcoma and fibrosarcoma are produced from a type of connective tissue known as mesenchyme. Cancers produced from muscle in the liver are leiomyosarcoma and rhabdomyosarcoma. Other less common liver cancers include carcinosarcomas, teratomas, yolk sac tumours, carcinoid tumours and lymphomas. Lymphomas usually have diffuse infiltration to liver, but It may also form a liver mass in rare occasions.
Many cancers found within the liver are not true liver cancers, but are cancers from other sites in the body that have spread to the liver (known as metastases). Frequently, the site of origin is the gastrointestinal tract (such as colon cancer and carcinoid tumors mainly of the appendix), but also from breast cancer, ovarian cancer, lung cancer, renal cancer, prostate cancer
Signs and symptoms
Because liver cancer is an umbrella term for many types of cancer, the signs and symptoms depend on what type of cancer is present. Cholangiocarcinoma is associated with sweating, jaundice, abdominal pain, weight loss and liver enlargement. Hepatocellular carcinoma is associated with abdominal mass, abdominal pain, emesis, anemia, back pain, jaundice, itching, weight loss and fever
Viral infection with either hepatitis C virus (HCV) or Hepatitis B virus (HBV) is the chief cause of liver cancer in the world today, accounting for 80% of hepatocellular carcinoma (HCC). The viruses cause HCC because massive inflammation, fibrosis and eventual cirrhosis occurs within the liver. HCC usually arises after cirrhosis, with an annual incidence of 1.7% in cirrhotic HCV-infected individuals. Around 5-10% of individuals that become infected with HBV become chronic carriers, and around 30% of these acquire chronic liver disease, which can lead to HCC. HBV infection is also linked to cholangiocarcinoma. The role of viruses other than HCV or HBV in liver cancer is much less clear, although there is some evidence that co-infection of HBV and hepatitis D virus may increase the risk of HCC.
Many genetic and epigenetic changes are formed in liver cells during HCV and HBV infection, which is a major factor in the production of the liver tumours. The viruses induce malignant changes in cells by altering gene methylation, affecting gene expression and promoting or repressing cellular signal transduction pathways. By doing this the viruses can prevent cells from undergoing a programmed form of cell death (apoptosis) and promote viral replication and persistence.
In addition to virus-related cirrhosis described above, other causes of cirrhosis can lead to HCC. Alcohol intake correlates with risk of HCC, and the risk is far greater in individuals with an alcohol-induced cirrhotic liver. There are a few disorders that are known to cause cirrhosis and lead to cancer, including hereditary hemochromatosis and primary biliary cirrhosis.
Aflatoxin exposure can lead to the development of HCC. The aflatoxins are a group of chemicals produced by the fungi Aspergillus flavus (the name comes from A. flavus toxin) and A. parasiticus. Food contamination by the fungi leads to ingestion of the chemicals, which are very toxic to the liver. Common foodstuffs contaminated with the toxins are cereals, peanuts and other vegetables. Contamination of food is common in Africa, South-East Asia and China. Concurrent HBV infection and aflatoxin exposure increases the risk of liver cancer to over three times that seen in HBV infected individuals without aflatoxin exposure. The mechanism by which aflatoxins cause cancer is through genetic mutation of a gene required for the prevention of cancer: p53.
Other causes in adults
- High grade dysplastic nodules are precancerous lesions of the liver. Within 2 years, there is a risk of cancer arising from these nodules of 30-40%.
- Obesity has emerged as an important risk factor as it can lead to steatohepatitis.
- Diabetes increases the risk of HCC.
- Smoking increases the risk of HCC compared to non-smokers and previous smokers.
- There is around 5-10% lifetime risk of cholangiocarcinoma in people with primary sclerosing cholangitis.
- Liver fluke infection increases the risk of cholangiocarcinoma, and is the reason Thailand has particularly high rates of this cancer
Risk factors in children
Increased risk of liver cancer in children can be caused by Beckwith-Wiedemann Syndrome (associated with hepatoblastoma), familial adenomatous polyposis (associated with hepatoblastoma), low birth weight (associated with hepatoblastoma), Progressive familial intrahepatic cholestasis (associated with HCC) and Trisomy 18 (associated with hepatoblastoma).
Many imaging modalities are used to aid in the diagnosis of primary liver cancer. For HCC these include sonography (ultrasound), computed tomography (CT) and magnetic resonance imaging (MRI). When imaging the liver with ultrasound, a mass greater than 2 cm has more than 95% chance of being HCC. The majority of cholangiocarcimas occur in the hilar region of the liver, and often present as bile duct obstruction. If the cause of obstruction is suspected to be malignant, endoscopic retrograde cholangiopancreatography (ERCP), ultrasound, CT, MRI and magnetic resonance cholangiopancreatography (MRCP) are used.
Tumor markers, chemicals sometimes found in the blood of people with cancer, can be helpful in diagnosing and monitoring the course of liver cancers. High levels of alpha-fetoprotein (AFP) in the blood can be found in many cases of HCC and intrahepatic cholangiocarcinoma. Cholangiocarcinoma can be detected with these commonly used tumor markers: carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA) and cancer antigen 125 (CA125). These tumour markers are found in primary liver cancers, as well as in other cancers and certain other disorders.
Prevention of cancers can be separated into primary, secondary and tertiary prevention. Primary prevention preemptively reduces exposure to a risk factor for liver cancer. One of the most successful primary liver cancer preventions is vaccination against hepatitis B. Vaccination against the hepatitis C virus is currently unavailable. Other forms of primary prevention are aimed at limiting transmission of these viruses by promotion of safe injection practice, screening of blood donation products and screening of high risk asymptomatic individuals. Aflatoxin exposure can be avoided by post-harvest intervention to discourage mold, which has been effective in west Africa. Reducing alcohol abuse, obesity, and diabetes would also reduce rates of liver cancer. Diet control in hemochromatosis could decrease the risk of iron overload, decreasing the risk of cancer.
Secondary prevention includes both cure of the agent involved in the formation of cancer (carcinogenesis) and the prevention of carcinogenesis if this is not possible. Cure of virus-infected individuals is not possible, but treatment with antiviral drugs such as interferon can decrease the risk of liver cancer. Chlorophyllin may have potential in reducing the effects of aflatoxin.
Tertiary prevention includes treatments to prevent the recurrence of liver cancer. These include the use of chemotherapy drugs, and antiviral drugs
Surgical resection is often the treatment of choice for non-cirrhotic livers. Increased risk of complications such as liver failure can occur with resection of cirrhotic livers. 5-year survival rates after resection has massively improved over the last few decades and can now exceed 50%. Recurrence rates after resection due to the spread of the initial tumor or formation of new tumors exceeds 70%. Liver transplantation can also be used in cases of HCC where this form of treatment can be tolerated and the tumor fits specific criteria (such as the Milan criteria). Less than 30-40% of individuals with HCC are eligible for surgery and transplant because the cancer is often detected late stage. Also, HCC can progress during the waiting time for liver transplants, which can prevent transplant due to the strict criteria.
Percutaneous ablation is the only non-surgical treatment that can offer cure. There are many forms of percutaneous ablation, which consist of either injecting chemicals into the liver (ethanol or acetic acid) or producing extremes of temperature using radio frequency ablation, microwaves, lasers or cryotherapy. Of these, radio frequency ablation has one of the best reputations in HCC, but the limitations include inability to treat tumors close to other organs and blood vessels due to heat generation and the heat sync effect, respectively.
Systemic chemotherapeutics are not routinely used in HCC, although local chemotherapy may be used in a procedure known as transarterial chemoembolization. In this procedure, cytotoxic drugs such as doxorubicin or cisplatin with lipiodol are administered and the arteries supplying the liver are blocked by gelatin sponge or other particles. Because most systemic drugs have no efficacy in the treatment of HCC, research into the molecular pathways involved in the production of liver cancer produced sorafenib, a targeted therapy drug that prevents cell proliferation and blood cell growth. This drug provides a survival benefit for advanced HCC.
Radiotherapy is not often used in HCC because the liver is not tolerant to radiation. Although with modern technology it is possible to provide well targeted radiation to the tumor, minimizing the dose to the rest of the liver. Dual treatments of radiotherapy plus chemoembolization, local chemotherapy, systemic chemotherapy or targeted therapy drugs may show benefit over radiotherapy alone.
Resection is an option in cholangiocarcinoma, but less than 30% of cases of cholangiocarcinoma are resectable at diagnosis. After surgery, recurrence rates are up to 60%. Liver transplant may be used where partial resection is not an option, and adjuvant chemoradiation may benefit some cases.
60% of cholangiocarcinomas form in the perihilar region and photodynamic therapy can be used to improve quality of life and survival time in these unresectable cases. Photodynamic therapy is a novel treatment that utilitizes light activated molecules to treat the tumor. The compounds are activated in the tumor region by laser light, which causes the release of toxic reactive oxygen species, killing tumor cells.
Systemic chemotherapies such as gemcitabine and cisplatin are sometimes used in inoperable cases of cholangiocarcinoma.
Radio frequency ablation, transarterial chemoembolization and internal radiotherapy (brachytherapy) all show promise in the treatment of cholangiocarcinoma.
Radiotherapy may be used in the adjuvant setting or for palliative treatment of cholangiocarcinoma.
Removing the tumor by either surgical resection or liver transplant can be used in the treatment of hepatoblastoma. In some cases surgery can offer a cure. Chemotherapy may be used before and after surgery and transplant.
Chemotherapy, including cisplatin, vincristine, cyclophosphamide, and doxorubicin are used for the systemic treatment of hepatoblastoma. Out of these drugs, cisplatin seems to be the most effective.