All About Liver Cancer

What is the liver?

The liver is the largest solid organ in the body. It is found on the right side of the abdomen just beneath the right diaphragm. Organs that surround the liver include the gall bladder (located just behind the liver), the small intestine, part of the colon (large intestine), the right kidney, and the head of the pancreas. The liver is triangular in shape and is divided into a right and left lobe. The right lobe is larger than the left. It does many important jobs in the body including:

• Filters the blood to remove and process toxins.
• Makes and excretes bile, which is important in processing fat from our diet.
• Helps regulate blood sugar (glucose) levels.
• Produces factors that play an important role in blood clotting.

The liver is a very vascular organ, meaning it has a large number of blood vessels. It receives blood through two separate systems: the hepatic artery and the portal vein. Blood from the abdomen and lower body flow through the liver where it is processed. It then proceeds to the inferior vena cava and ultimately empties into the heart. In large part, due to the vascular nature of the liver, it is a very common site where cancers from other areas of the body spread (also known as metastasis).

What is liver cancer?

Normally, cells in the body will grow and divide to replace old or damaged cells. This growth is highly regulated, and once enough cells are produced to replace the old ones, normal cells will stop dividing. Tumors occur when there is an error in this regulation and cells continue to grow uncontrolled. Tumors of the liver occur when there is an error in the regulation of growth of any of the cells in the liver, including the liver cells themselves (hepatocytes), the bile duct cells, or the blood vessels within the liver.

Tumors can either be benign or malignant. Benign tumors grow uncontrolled. They do not break off and spread beyond where they started, and do not invade into surrounding tissues. There are a number of benign liver tumors. Hemangiomas are the most common benign tumor of the liver, and occur when a benign, blood-filled tumor forms within the liver. Other benign tumors include adenomas (benign tumors of the hepatocytes) and focal nodular hyperplasia (a localized growth of several types of liver cells). Although these tumors do not invade surrounding tissues or metastasize, it is often hard to tell if a tumor is benign and malignant on imaging.

In contrast, malignant tumors invade and damage other tissues around them. They can also break off from where they started and spread to other parts of the body (metastasize). This usually happens through the bloodstream or through the lymphatic system where the lymph nodes are located. Over time, the cells of a malignant tumor become more abnormal and appear less like normal cells. This change in the appearance of cancer cells is called the tumor grade, and cancer cells are described as being well-differentiated, moderately-differentiated, poorly-differentiated, or undifferentiated. Well-differentiated cells are fairly normal appearing and resemble the normal cells from which they started. Undifferentiated cells are cells that have become so abnormal that, we cannot tell what types of cells they started from.

When malignant tumors start in the liver this is primary liver cancer. Secondary liver tumors, or liver metastases, are cancers that start elsewhere in the body and metastasize (spread) to the liver. There are many different types of liver cancer:

• Hepatocellular carcinoma (HCC): arises from the hepatocytes. This is the most common type of primary liver cancer. These cancers can arise from the bile ducts within the liver (known as intrahepatic cholangiocarcinomas) or from the bile ducts as they lead away from the liver (known as extrahepatic cholangiocarcinomas). This article focuses on HCC. Learn more about cholangiocarcinomas here.
• Hemangiosarcomas: malignant blood-filled tumors.
• Hepatoblastoma: a rare cancer that develops in very young children.
• Fibrolamellar liver cancer: a rare cancer that occurs in teens and young adults with no history of liver disease. Learn more about childhood liver cancers here.

What causes liver cancer and am I at risk?

Each year in the United States, there are about 42,230 new diagnoses of liver cancer(including hepatocellular and cholangiocarcinoma). Liver cancer is much more common in other areas of the world, particularly in sub-Saharan Africa and Southeast Asia. Worldwide, there are 700,000 people diagnosed with liver cancer each year. The number of people who develop liver cancer is increasing both abroad and in the United States.

There are a number of risk factors related to liver cancer. In the United States, the most common risk factor for liver cancer is liver cirrhosis. Cirrhosis results from scar formation within the liver. This is most often due to chronic alcohol use or chronic infection with hepatitis C virus (HCV). Worldwide, other risk factors, such as chronic infection with hepatitis B virus (HBV) and aflatoxin B1 food contamination are more common. Aflatoxin is a toxic chemical that is made by a fungus commonly seen in tropical regions. The presence of the fungus on food in these regions leads to chronic exposure to the toxin, resulting in an increased risk of developing liver cancer.

Tobacco use has also been associated with increased risk. Other environmental factors include the use of anabolic steroids, exposure to vinyl chloride, arsenic, and thorium dioxide (Thorotrast), a contrast agent previously used for radiographic imaging that is no longer used.

Several inherited diseases can increase the risk of liver cirrhosis and therefore increase the risk of developing liver cancer. These diseases include: 

• Hemochromatosis: the body absorbs and stores too much iron. 
• Wilson's disease: the body retains too much copper. 
• Alpha-1-antitrypsin deficiency: a deficiency in a key enzyme that can lead to emphysema of the lung and cirrhosis of the liver. 

Patients with a family history of liver cancer may also be at increased risk. Males are about twice as likely to develop liver cancer as females. This may be due to a genetic predisposition of males for liver cancer, but may also be due to the fact that males are more likely to be exposed to the risk factors discussed above.

There is growing evidence for a link between the damage caused by non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (liver inflammation) and metabolic syndrome (a combination of conditions, including high blood pressure, blood sugar and cholesterol, and excess fat around the waist) in the development of hepatocellular cancer and research into these risk factors is ongoing.

How can I prevent liver cancer?

The best way to prevent liver cancer is to avoid the risk factors that are associated with it. Avoid excessive use of alcohol and quit smoking to reduce the risk of liver cancer. Preventing and treating HBV and HCV infections is also important. A vaccine for HBV is available and people who are at high risk for exposure to the virus (such as health care workers and individuals with high-risk sexual practices) should be vaccinated. HCV is spread through blood transfusions, unprotected sexual intercourse, and through the sharing of needles by individuals with substance abuse disorders. There is no vaccine for HCV so you should avoid the risk factors for infection. Once infected with HBV or HCV, treatment of the infection can reduce the risk of developing liver cancer.

In other parts of the world, changing the way that foods are stored and processed can decrease the risk of aflatoxin exposure. Proper treatment of water can reduce the risk of arsenic in drinking water. Appropriate treatment of inherited diseases associated with cirrhosis and liver cancer can reduce the risk of developing either cirrhosis or liver cancer. While the risk of liver cancer can never be reduced to zero, it can be greatly reduced by avoiding known risk factors.

What screening tests are used for liver cancer?

Currently, there is no approved screening test for liver cancer. One potential screening test involves blood levels of alpha-fetoprotein (AFP). AFP is a protein that is found at high levels in fetal blood, but normally goes away once the baby is born. AFP levels increase in the presence of HCC and can be a marker of the development of liver cancer. While some patients who are at high risk for developing liver cancer are routinely tested for AFP levels, this is generally not a good screening tool. Not all liver cancers make high levels of AFP in the blood, and by the time most patients are found to have high AFP levels, the tumor is already at an advanced stage.

Other blood proteins may potentially be used as screening tools for liver cancer. Several studies have shown the use of proteins such as des-gamma-carboxy prothrombin (DCP) and Lens culinaris agglutinin-reactive fraction (AFP-L3) may also be used as markers of liver cancer formation. However, in practice, these are not often used. More studies with these and other proteins are needed before they can be used more extensively for liver cancer screening.

In general, it is reasonable for individuals at high risk for liver cancer to be screened. This includes those infected with HBV or HCV, those with a known history of liver cirrhosis, and patients with inherited diseases known to be associated with cirrhosis. In these individuals, annual AFP levels are often followed and if AFP levels are found to rise from one year to the next, appropriate follow-up testing should be ordered. Also, individuals with cirrhosis often undergo routine screening with an ultrasound of the liver. It is important to note that when a patient with long-standing liver cirrhosis suddenly gets worse, liver cancer is often the cause. The Child-Pugh score is a system of grading the degree of cirrhosis, with a range from A (least impaired) to C (most impaired), and helps guide providers as to which treatments are appropriate.

What are the signs of liver cancer?

Liver cancer usually does not cause a lot of symptoms until the cancer is quite advanced. Because of this, early-stage liver cancers are rarely detected. If you do develop symptoms, you may have:

• Abdominal pain.
• Feelings of abdominal fullness or bloating. This can be due to ascites which is a collection of fluid within the abdominal cavity.
• Fatigue.
• Loss of appetite.
• Nausea and vomiting.
• Yellowing of the skin/eyes (jaundice).
• Weight loss.

The symptoms of liver cancer can be associated with many other illnesses. If you are having any symptoms it is best to contact your provider for evaluation. 

How is liver cancer diagnosed?

When liver cancer is suspected, your healthcare provider will perform a thorough history and physical examination. If a liver tumor is suspected or you are at a higher risk for developing liver cancer, a number of diagnostic tests may be performed:

• An ultrasound is a test that uses sound waves to produce an image of the inside of the body. Ultrasounds are often used to screen for and diagnose liver cancers because they are very easy to perform and have little to no risk to the patient.
• Computed tomography (CT/CAT scan) is often used to diagnose liver cancers. CT scans are very useful in diagnosing liver tumors. However, it is hard to tell a benign tumor from malignant tumor on CT scan. CT scans often give more detailed images than ultrasounds and are often used to help diagnose liver cancers.
• An MRI may be used if there is difficulty seeing a tumor on CT or ultrasound, or if there is a question about whether a tumor is benign or malignant. 
• Angiography is a procedure in which a small tube (called a catheter) is threaded into a blood vessel, often placed through the groin. Contrast is injected directly into the blood vessels leading to the liver and x-rays are taken that can show highly vascular liver tumors. This procedure is not often used because it is much more invasive than ultrasound, CT, or MRI.

An elevated alpha-fetoprotein (AFP) can increase the suspicion that a tumor is malignant if it is unclear via imaging. Other blood tests can help determine the extent of liver involvement or if there are pre-existing liver conditions that would predispose a patient to develop liver cancer. These include liver function tests such as AST, ALT, total bilirubin, and albumin.

The most important diagnostic test for liver cancer is a biopsy. To perform a biopsy, a piece of the tumor is removed and looked at under a microscope in the laboratory. There are many ways a liver biopsy can be done:

• Exploratory laparotomy: where the surgeon makes a long incision (cut) to look at the organs in the belly, including the liver. 
• Laparoscopy: a fiberoptic camera is placed through a small hole in the abdomen and using this camera to help find where the biopsy needs to be taken. 
• Under the guidance of ultrasound, CT, or MRI where a long needle is used to remove a small piece of the tumor tissue. 
• Transvenous biopsies: when a  catheter is inserted into a vein (usually in the neck) and the catheter is guided through veins to the liver. A needle within the catheter is used to obtain a piece of the tumor. 

After the biopsy the tissue is sent to a pathologist who looks at the tissue under a microscope to determine whether the tumor is cancerous or not. This information is reported in a pathology report.

How is liver cancer staged?

Once a diagnosis of liver cancer is made, more tests should be ordered to determine the extent of the disease. A CT scan or MRI of the abdomen and pelvis should be done to look for abnormally enlarged lymph nodes, which can result from the spread of cancer, and to look for metastatic disease. Other laboratory tests may also be done to look for specific tumor markers associated with liver cancer.

The staging of liver cancer is quite complex and may involve multiple assessment tools that look at not only the size and spread of the tumor but also how well the liver is working. As more targeted therapies have become available to treat liver cancers that are not operable, it has become more important to know more about the extent of the tumor as described in the TNM staging system, described by the American Joint Committee on Cancer. The TNM systems are used to describe many types of cancers. They have three components

• T-describes the size/location/extent of the "primary" tumor in the esophagus.
• N-describes if the cancer has spread to the lymph nodes
• M-describes if the cancer has spread to other organs (i.e.-metastases). 

The staging system is very complex. The entire staging system is outlined at the end of this article. Though complicated, the staging system helps healthcare providers determine the extent of the cancer, and in turn, make treatment decisions for your cancer. 

Beyond the AJCC staging system, there are many other staging systems used in the diagnosis and treatment planning of liver cancer. The Child-Pugh score helps to determine how well the liver is working. It evaluates the severity of the liver disease. Points (from 1-3) are assigned for each of the following: evidence of ascites (fluid in the abdomen), encephalopathy (confusion), bilirubin and albumin levels, and bleeding time. These points are combined to give a total score ranging from 5-15. Based on the number score, a letter grade of A, B, or C is assigned. A Child-Pugh score of A indicates good liver function, whereas C means that the liver is not working well.

There are other staging systems for liver cancer, such as the Barcelona Clinic Liver Cancer (CLIP) staging system, which takes into account how well the patient’s liver is working (using the Child-Pugh score) and other prognostic indicators, unlike the AJCC system. The Milan and USCF systems may also be used for staging, especially in patients who are being evaluated for liver transplant.

Although the systems of cancer staging are quite complicated, they are designed to help your healthcare providers describe the extent of cancer, and therefore, help to direct what type of treatment is given.

How is liver cancer treated?

Surgery

Surgery can be used to treat liver cancer. However, surgery is a good option only if the cancer has not spread beyond your liver. Liver cancer surgery can consist of either resection of a portion of the liver (known as a partial hepatectomy) or removal of the whole liver followed by liver transplantation. The type of surgery that is done depends on the location of the tumor, the size of the tumor, and the overall health of the patient. It is common for liver cancer to have grown or spread to a point where surgery is not possible. It is common for patients with liver cancer to have other medical problems such as cirrhosis, causing them to not be healthy enough to have surgery.

In general, only patients with good liver function can tolerate a partial hepatectomy. For patients with poor liver function or who have extensive cirrhosis, liver transplantation is an option unless the cancer is too extensive or in a location that makes transplantation too difficult. Transplantation can treat both cancer and underlying liver disease. However, the number of liver donors is far smaller than the number of patients who may benefit from a liver transplant. Often, patients who would be good candidates for liver transplantation, are unable to receive them due to the lack of available organs.

Local Treatments

For patients with tumors that have not spread beyond the liver, but cannot undergo resection of the tumor due to its location, a number of local treatments are used. These include cryosurgery/ablation, radiofrequency ablation, ethanol injections, transarterial chemoembolization, and radioembolization. Your team will determine if these treatment options are available based on the size and location of your tumor.

Cryosurgery

In cryosurgery, liquid nitrogen or argon is used to cool probes that are inserted directly into the tumor during an operative procedure. The probes freeze the cancer cells, killing them. This technique has the advantage of treating very little normal tissue, thereby reducing the risk of side effects from the treatment. However, it can only be used to treat tumors that can be seen by the naked eye (no more than 5 tumors that measure less than 5 cm) or by ultrasound and requires an operation to perform.

Radiofrequency Ablation (RFA)

Another local treatment for liver cancer is radiofrequency ablation (RFA). Radiofrequency ablation consists of inserting a probe directly into the tumor and killing cancer cells with the use of electrodes that are inside the probe. These electrodes emit high-energy heat. This technique can be performed through the skin and does not always require an open operation (although it can be performed during surgery as well). However, technically, it is more difficult to perform than cryosurgery. It is used on tumors less than 3 cm.

Ethanol Injections

Ethanol injections involve injecting ethanol (alcohol) directly into tumors using small needles. The high concentration of ethanol used in these injections can result in the killing of the tumor cells. Only small tumors (less than 2 cm, no larger than 5 cm) can be treated in this manner. In patients with a small number of small tumors, ethanol injections can result in reasonable rates of tumor control. In general, in the US, RFA has replaced ethanol injections.

Arterially Directed Therapies

Chemoembolization of the hepatic artery takes advantage of the fact that many liver cancers receive a large portion of their blood supply through the hepatic artery. By injecting chemotherapy through a catheter into the hepatic artery, the blood flow through the artery is blocked and the blood supply to the tumor is disrupted. The use of hepatic artery embolization is still being studied for use in patients with both resectable and unresectable liver cancer. It is first-line therapy for multifocal tumors in patients with Child-Pugh class A liver disease.

Radioembolization combines radiation therapy and embolization by using a radioactive isotope, yttrium y-90 to deliver radiation directing to the blood vessels that feed the tumor. This is given through microspheres, which are tiny glass or resin beads, filled with yttrium Y-90. Once inside the blood vessels, the blood supply is to the tumor is blocked, but the healthy tissue around the tumor is spared.

Radiation Therapy

Another treatment for liver cancer is radiation therapy. Radiation therapy uses high energy rays (similar to x-rays) to kill cancer cells. The high energy of x-rays in radiation therapy results in damage to the DNA of cells. Cancer cells do not repairing DNA damage as well as healthy cells so radiation damages cancer cells more than normal cells. This can help spare normal tissue.

Radiation therapy can affect a large part of the healthy liver. Because of this, radiation is not used to treat liver cancers. It can be used when other treatment options have failed, or when the liver cancer has spread to another part of the body and is causing side effects such as pain in a bone. Research is being done to find ways of improving the delivery of radiation to liver cancers. These include the use of breath-holding techniques, stereotactic body radiation, radiosensitizers (chemicals that are given together with radiation to improve the sensitivity of liver cancers to radiation), and radiolabeled antibodies (radioactive molecules attached to antibodies that specifically find and attach to liver cancer cells). Radiation therapy may be given along with Sorafenib (oral chemotherapy) or chemoembolization. When chemoembolization is combined with radiation, outcomes are improved compared to chemoembolization alone. Proton beam therapy is also being investigated in hepatocellular cancer as part of the treatment plan.

Chemotherapy

Chemotherapy is a medication that is usually given intravenously (into a vein) or as a pill. It goes to the bloodstream and throughout the body to kill cancer cells. This is one of the big advantages of chemotherapy. If cancer cells have broken off from the tumor and are somewhere else inside the body, chemotherapy has the chance of finding those cells and killing them. Liver cancers are relatively resistant to cytotoxic chemotherapy, making treatment with chemotherapy a challenge. Chemotherapy is often processed within the liver, and a decrease in liver function can make the delivery of chemotherapy more difficult.

Chemotherapy may be used in liver cancer when cancer has spread outside of the liver. However, the overall effectiveness of this treatment has been limited. It can also be used in the adjuvant setting, after surgical resection of a tumor that has not spread beyond the liver. Despite the advantages of chemotherapy after surgery, a number of studies have failed to show an improvement in tumor control with the use of adjuvant chemotherapy (chemo given after surgery). Atezolizumab in combination with bevacizumab, sorafenib, regorafenib, cabozantinib, ramucirumab, nivolumab, ipilimumab and lenvatinib are used in the treatment of liver cancer. Your provider will treat your tumor based on its size, location, stage and Child-Pugh class.

Several different chemotherapy drugs have been studied for patients who have an unresectable disease (not eligible for surgery), including 5-FU, oxaliplatin, doxorubicin, cisplatin, capecitabine, and thalidomide. They can be used in combination or by themselves. They have not been found to be very effective in treating hepatocellular cancer. 

Clinical Trials

Clinical trials are extremely important in furthering our knowledge of this disease. It is through clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your healthcare provider about participating in clinical trials in your area. You can also explore currently open clinical trials using the OncoLink Clinical Trials Matching Service. 

Follow-Up Care and Survivorship

Close follow-up after treatment for liver cancer is critical. There is a high rate of recurrence in individuals who have been previously treated. There is also a high risk of developing a second liver cancer in patients with severe liver cirrhosis. It is recommended that follow-up care be performed every 3-6 months for the first two years following treatment, then every 6-12 months. Follow-up care should include treatment of underlying medical problems such as hepatitis or alcoholism, routine blood tests including blood markers such as AFP, and radiographic imaging such as CT scans and MRIs. You should report any concerning signs or symptoms to your healthcare team right away.

Fear of recurrence, relationships and sexual health, the financial impact of cancer treatment, employment issues, and coping strategies are common emotional and practical issues experienced by liver cancer survivors. Your healthcare team can identify resources for support and management of these challenges faced during and after cancer.

Cancer survivorship is a relatively new focus of oncology care. With nearly 17 million cancer survivors in the US alone, there is a need to help patients transition from active treatment to survivorship. What happens next, how do you get back to normal, what should you know and do to live healthy going forward? A survivorship care plan can be a first step in educating yourself about navigating life after cancer and helping you communicate knowledgeably with your healthcare providers. Create a survivorship care plan today on OncoLink.

Resources for More Information

American Liver Foundation Educational resources and support services for liver disease.

Appendix: Complete Liver Cancer Staging

AJCC, Cancer Staging Manual, 8th Edition

The healthcare team may also utilize the histologic grade to help determine which targeted therapies may be best suited to treat the tumor if it is unresectable. Histology refers to the way the tumor cells look under a microscope.

Child-Pugh Score

Class A= 5-6 Points; Good operative risk

Class B= 7-9 Points; Moderate operative risk

Class C= 10-15 Points; Poor operative risk