Liver Cancer

Although there are several factors that can increase risk of liver cancer, it is not fully understood how these factors might cause liver cancer. Some risk factors, such as viral infections and exposure to toxins, may change or damage the DNA within liver cells. This may result in the cells growing and dividing uncontrollably, which may lead to liver cancer. However, the exact cause of liver cancer is unknown.

Risk factors include:

• Sex—men are more likely than women to develop HCC, while the fibrolamellar subtype of HCC is more common in women.
• Race or Ethnicity—in the U.S., Asian Americans and Pacific Islanders are more likely to develop HCC.
• Underlying diseases or conditions—a number of health conditions can raise the risk of developing liver cancer:
  • Type 2 diabetes—type 2 diabetes has been linked to a higher risk of liver cancer, though it usually develops in people with diabetes who have additional risk factors.
  • Cirrhosis—all of the conditions listed below can, if they are present long enough, lead to cirrhosis, a disease in which liver cells are replaced by scar tissue after damage. Except for hepatitis B, most of the other causes of HCC listed below only cause cancer when patients have developed cirrhosis.
    • Chronic viral hepatitis—the most common risk factor for HCC is a chronic hepatitis B or hepatitis C infection, which can lead to cirrhosis of the liver. In the U.S., hepatitis C is more common than hepatitis B as a cause of liver cancer.
    • Nonalcoholic steatohepatitis (NASH)—this condition is caused by a significant build-up of fat in the liver, resulting in inflammation and damage. Eventually, it can become severe and lead to cirrhosis.
    • Inherited or rare diseases—examples include:
      • Alpha-1 antitrypsin deficiency
      • Porphyria cutanea tarda
      • Glycogen storage diseases
      • Wilson disease
      • Hereditary hemochromatosis
  • Primary sclerosing cholangitis (PSC)—this is a chronic, slowly progressing disease that is marked by inflammation, scarring, and damage of the bile ducts. The bile ducts can become blocked, causing bile to buildup in the liver, which can result in liver damage. PSC can lead to tumors of the bile duct or liver.
• Exposure to chemicals, toxins or other harmful substances—examples of these include:
  • Eating food that contains aflatoxins, substances made by a fungus that contaminates certain crops (e.g., grains, nuts) that have not been stored properly. This is a risk factor for HCC.
  • Vinyl chloride—a risk factor for angiosarcoma
  • Thorium dioxide—also a risk factor for angiosarcoma
• Lifestyle factors—examples include:
  • Heavy alcohol drinking (which may also cause cirrhosis)
  • Tobacco use, such as cigarette smoking
  • Obesity

Liver cancer's signs and symptoms typically don't appear until later stages, making it hard to detect the disease early. Most of the liver is covered by the right rib cage, so by the time a tumor is large enough to be felt, the disease is advanced.

Most of the signs and symptoms of liver cancer can be vague and caused by other conditions. Examples include:

• Loss of appetite or weight loss without trying
• Feeling full after a small meal
• Nausea or vomiting
• A feeling of fullness under the ribs on either side
• Pain in the abdomen or near the right shoulder blade
• Abdominal swelling or bloating
• Itching
• Jaundice—yellowing of the skin and whites of the eyes
• Fever
• Enlarged veins on the abdomen that can be seen through the skin
• Abnormal bruising or bleeding
• White, chalky stools

Additionally, some liver tumors produce hormones that affect other organs, and these hormones can cause:

• High blood calcium (hypercalcemia)—this can cause nausea, constipation, muscle problems (including weakness) and confusion.
• Low blood glucose (hypoglycemia)—this can cause fainting and fatigue.
• High red blood cell count—this can cause you to look red or flushed.

The goals of testing are to aid in diagnosis, staging, assessing treatment options, and monitoring treatment of liver cancer. A combination of laboratory testing and imaging tests may be used to evaluate your liver and liver function.

Screening
There are currently no recommendations to screen people who are at an average risk for liver cancer. However, many general medical exams (e.g., annual physical) include "liver tests" that can help evaluate overall liver health.

If you are at higher risk — for example, if you have cirrhosis or a disease such as chronic hepatitis B infection — your healthcare practitioner may want to screen for liver cancer every six months. Early diagnosis can significantly improve chances of survival. Screening may include:

• An ultrasound exam to look at the liver and help detect tumors
• Alpha-fetoprotein (AFP) blood test—the level of AFP in the blood can be increased with HCC but also with other cancers or liver damage and disease with other causes.

Diagnosis and Staging

Imaging scans
If a healthcare practitioner suspects liver cancer, they will typically use imaging tests to view the abdomen and liver and look for suspicious areas or tumors. A diagnosis of liver cancer may sometimes be based on results of imaging scans, such as:

• Ultrasound
• Computed tomography (CT)
• Magnetic resonance imaging (MRI)

Additionally, these tests can help determine how far cancer might have spread. A healthcare practitioner may also order an angiogram, which is an X-ray test that looks at blood vessels to show arteries that supply blood to a tumor. This is typically done to evaluate whether it may be possible to directly inject chemotherapy into the liver to treat an HCC.

For more information on these imaging procedures, see RadiologyInfo.org.

Liver biopsy
A biopsy may be performed to remove a sample of tissue from the liver. A pathologist uses a microscope to examine the tissue and determine if cancer is present. (For in-depth information, see the article on Anatomic Pathology.) However, if a healthcare practitioner is relatively certain liver cancer is present through other tests, such as imaging scans and blood tests, a biopsy might not be done. There may be a concern that the procedure could cause the cancer to spread to other parts of the body.

If needed, a biopsy can be done in various ways:

• Fine-needle aspiration biopsy—a healthcare practitioner inserts a thin needle into the liver and removes some cells from the tumor.
• Needle biopsy—a healthcare practitioner inserts a slightly larger needle to remove a small amount of the tumor.
• Laparoscopic biopsy—a thin, flexible tube with a light and a small camera on the end is inserted through a small cut near the navel. Samples of tissue can be removed from abnormal areas of the liver during laparoscopy.
• Surgical biopsy—surgery may be performed to remove a piece of the tumor (incisional biopsy) or to remove the entire tumor plus some surrounding normal liver tissue (excisional biopsy).

Laboratory tests

Tumor markers
Tumor markers are substances, often proteins, that are produced by the cancer tissue itself or sometimes by the body in response to cancer growth. There are two tumor markers related to liver cancer that can be detected in blood, so these markers may be used, along with other tests and procedures, to help detect and diagnose liver cancer, predict and monitor response to treatment, and detect recurrence. They include:

• Alpha-fetoprotein (AFP)—a healthcare practitioner who suspects liver cancer based on your medical history, physical exam and/or imaging scans might order an AFP tumor marker test. When levels are high in a person with a liver mass, it might mean that cancer is present. However, many patients with early liver cancer do not have high levels of AFP. If AFP is elevated, the AFP test may be ordered multiple times during treatment, as decreasing levels of AFP can be a sign that treatment is working. After treatment, increasing levels can be a sign that the cancer has returned.
• Des-gamma-carboxy prothrombin (DCP)—may be used along with AFP to monitor the effectiveness of treatment and monitor for recurrence of liver cancer after successful treatment.

Additional lab tests may be performed to evaluate liver function and your general health. Examples include:

• Liver panel—to determine the condition of your liver
• Hepatitis B and hepatitis C tests—to detect these liver infections, especially chronic forms
• Prothrombin time (PT)—to evaluate blood clotting function; the liver produces most of the clotting proteins (coagulation factors) that help regulate bleeding and clotting, so liver cancer can significantly affect the blood clotting system.
• Complete blood count (CBC)—to evaluate red blood cells, white blood cells and platelets
• Comprehensive metabolic panel (CMP)—includes several tests that evaluate your liver

Liver cancer is divided into stages that describe the tumor's size, how many tumors are present, and how far the tumor has spread through the body. Stages of liver cancer range from Stage I (1) to IV (4). Generally, the lower the number, the less the cancer has spread. Staging is important for determining treatment and prognosis.

Cancer that is staged based on the result of a physical exam, biopsies and imaging tests is known as a clinical stage. If surgery is done, a pathologist determines pathologic, or surgical stage, by using a microscope to examine the tissue removed. (For more detail, see the section on "Biopsies and examination of tissues" in the Anatomic Pathology feature article.)

There are several different systems used to stage liver cancer, and some take into account liver function. In the U.S., healthcare practitioners typically use the staging system from the American Joint Committee on Cancer (AJCC). Liver cancer staging is complex but generally, one of four stages of cancer is identified. They are:

• Stage 1—a single tumor of any size that hasn't grown into the blood vessels and has not spread to nearby lymph nodes or other parts of the body (e.g., lungs, bones)
• Stage 2—either a single tumor that is larger than 2 centimeters (4/5-inch) that has grown into blood vessels or more than one tumor but none larger than 5 centimeters (about 2 inches) across; the tumor or tumors have not spread to nearby lymph nodes or other parts of the body.
• Stage 3—more than one tumor, with at least one tumor larger than 5 centimeters across (about 2 inches) or at least one tumor of any size that has grown into a major branch of a large vein of the liver (the portal or hepatic vein); the tumor or tumors have not spread to nearby lymph nodes or other parts of the body.
• Stage 4—cancer that has spread to nearby lymph nodes and/or other parts of the body such as the bones or lungs

For a more detailed explanation of these stages, see the American Cancer Society's Liver Cancer Stages.

In America, healthcare practitioners often use the AJCC's staging system to determine the spread of liver cancer but use a different system to determine potential treatment. The four categories are:

1. Potentially resectable or transplantable—may be treated by surgery; if the cancer is in the early stage and a portion of your liver is still healthy, a partial hepatectomy—a surgery to remove part of the liver—can cure the disease. This type of treatment is seldom used for HCC because the liver is almost never healthy enough to allow this. If the entire liver is diseased, doctors may choose to do a liver transplant. Candidates for a liver transplant must have a tumor that is stage 1 or 2; otherwise, there is a higher risk of the cancer returning.

2. Unresectable—this means that the cancer hasn't spread to the lymph nodes or other parts of the body, but can't be safely removed by surgery because it is too large, in a part of a liver that makes it hard to remove, or there are several tumors within the liver. Treatment options are the same as for the next category below.

3. Inoperable with only local disease—this means that the cancer is small and could be removed by surgery, but the patient isn't healthy enough for an operation. Treatment options include:

• Ablation—use of radio waves, electromagnetic waves and heat, or alcohol directly on the tumor to shrink the tumor or prevent its growth.
• Embolization—uses substances to stop the flow of blood to a tumor; this may be combined with chemotherapy that is injected into the same region (often referred to as transcatheter chemoembolization or TACE).
• Targeted therapy—use of drugs to target specific types of cancer cells without causing as much harm to normal cells; one example is tyrosine kinase inhibitors (TKIs).
• Immunotherapy—treatments that use the body's immune system to fight the cancer; an example is drug that is an immune checkpoint inhibitor that targets PD-L1.
• Chemotherapy—drugs injected into the bloodstream to kill cancer cells
• Radiation therapy—use of radiation directed at the tumor to kill it/them; this is more commonly used with liver cancers other than HCC.

4. Advanced, or metastatic, liver cancers can't be treated with surgery because they are widespread throughout the body. For well-functioning livers, targeted therapy drugs can help control the tumor's growth. Chemotherapy and radiation therapy may also be treatment options.