All About Liver Cancer
What is the liver?
The liver is the largest solid organ of the body.Itis located on the right side of the abdomen just beneath the right diaphragm. Surrounding organs 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 being the larger of the two. It provides several important functions to the body including:
- Filtering the blood to remove and process toxins.
- Synthesizing and excreting bile, which is important in processing fat from our diet.
- Helping regulate blood sugar (glucose) levels.
- Producing factors that play an important role in blood clotting.
The liver is a very vascular structure, containing a large number of blood vessels, and receives blood through two separate systems: the hepatic artery and the portal vein. Blood from the abdomen and lower body flows 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 the vascular nature of the liver, it is a very common site to which 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. Malignant tumors, however, will invade and damage other tissues around them. They can also gain the ability to break off from where they started and spread to other parts of the body (metastasize), usually through the blood stream 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 quite normal appearing and resemble the normal cells from which they originated. Undifferentiated cells are cells that have become so abnormal that, we cannot tell what types of cells they started from.
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 difficult to tell the difference between benign and malignant tumors on radiographic imaging.
When tumors originate in the liver this is primary liver cancer. Secondary liver tumors, or liver metastases, are cancers that originate elsewhere in the body and metastasize (spread) to the liver. In addition to being a common site of metastasis for cancers from other sites in the body, primary liver cancers can arise from within the liver itself. Cancer arising from the hepatocytes is known as hepatocellular carcinoma (HCC). It 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 in the bile ducts as they lead away from the liver (known as extrahepatic cholangiocarcinomas). Other types of rare cancers can occur within the liver. These include hemangiosarcomas (malignant blood-filled tumors), hepatoblastoma (a rare cancer that develops in very young children), and fibrolamellar liver cancer (rare cancer that occurs in teens and young adults with no history of liver disease).
What causes liver cancer and am I at risk?
Annuallyin the United States, there are an estimated 42,030 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 700,000people diagnosed with liver cancereach 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 that are associated with 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, most commonly 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 produced by a fungus commonly seen in tropical regions. 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; however, it is not as strong of a risk factor as liver cirrhosis. Other environmental factors include 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 (where the body absorbs and stores too much iron), Wilson's disease (where the body inappropriately retains too much copper), and 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. Finally, 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.
How can I prevent liver cancer?
The best way to prevent liver cancer is to avoid the risk factors that are associated with it. Avoiding the excessive use of alcohol and quitting smoking can 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 intercourse, and through the sharing of needles by IV drug users. Although there is no vaccine for HCV, avoiding the means by which it is spread can significantly reduce the risk of being infected. Once infected with HBV or HCV, appropriate treatment of the infection can reduce the risk of developing liver cancer.
In other parts of the world, altering 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 significantly 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 involvesblood levels of alpha-fetoprotein (AFP). AFP is a protein that is found at high levels in fetal blood, but normally disappears 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 produce 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 infrequently used. Additional 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 patients at high risk for liver cancer to be screened. These patients include 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 patients, 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. In addition, patients with cirrhosis often undergo routine screening with ultrasound of the liver. It is important to note that when a patient with long-standing liver cirrhosis suddenly gets worse, liver cancer is frequently a 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 physicians 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. When patients do develop symptoms, they may have:
- Abdominal pain.
- Feelings of abdominal fullness or bloating.This can bedue to ascites which is a collection of fluid within the abdominal cavity.
- Loss of appetite.
- Yellowing of the skin/eyes (jaundice).
- Weight loss.
The symptoms of liver cancer can be associated many other illnesses. If you are experiencingany symptoms it is best to contact your provider for evaluation.
How is liver cancer diagnosed?
When liver cancer is suspected, the healthcare provider will perform a thorough history and physical examination. If a liver tumor is suspected or a patient is at high risk for developing a 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 internal 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, many benign tumors are often difficult to distinguish from malignant tumors 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 infrequently performed because it is much more invasive in nature than ultrasound, CT, or MRI.
An elevated alpha-fetoprotein (AFP), found through blood tests, 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 arepre-existing liver conditions that would predispose a patient to developing liver cancer. These includeliver functions tests such as AST, ALT, total bilirubin and albumin.
Ultimately, the most important diagnostic test for liver cancer is a biopsy. To perform a biopsy, a piece of the tumor is removed and evaluated in the laboratory. This can be done surgically during an exploratory laparotomy, where the surgeon makes a long incision to expose the abdominal contents (including the liver) for inspection. A surgeon can also perform a biopsy by laparoscopy, inserting a fiberoptic camera through a small hole in the abdomen and using this camera to help find where the biopsy needs to be taken. Biopsies can also be performed under the guidance of ultrasound, CT, or MRI where a long needle is used to removea small piece of the tumor tissue. Transvenous biopsies can be performed by inserting a catheter into a vein (usually in the neck) and guiding the catheter through veins to the liver. A needle within the catheter is used to obtain a piece of the tumor. Whatever the procedure used to obtain the biopsy, the tissue is then 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, additional tests should be ordered to determine the extent of the disease. A CT scan or MRI of the abdomen and pelvis should be performed if it hasn't already been done, to look for abnormally enlarged lymph nodes, which can result from spread of the cancer, and to examine 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 the combinationof multiple assessment tools that look at not only the size and spread of the tumor, but also the functional abilities of the liver. 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. This system is determined by the American Joint Committee on Cancer (AJCC). The "T stage" represents the extent of the primary tumor itself. The "N stage" represents the degree of involvement of the lymph nodes. The "M stage" represents whether or not there is spread of the cancer to distant parts of the body. Once the TNM stages are decided upon, the liver tumor is given a numeric stage, from I-IV, with I representing early stage disease and IV representing later stage disease. The complete AJCC staging system for liver tumors is listed at the end of this article.
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 the functional status of the liver. It evaluates the severity of 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 patients' liver function (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 transplantation.
Although the systems of cancer staging are quite complicated, they are designed to help your healthcare providers describe the extent of the cancer, and therefore, help to direct what type of treatment is given.
How is liver cancer treated?
Surgery provides the best chances for cure for patients with liver cancer; however, only patients with cancer that has not spread beyond the liver are candidates for surgical resection. 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 performed depends on the location of the tumor, the size of the tumor, and the overall health of the patient. Unfortunately, it is common for liver cancer to have grown or spread to a point where surgery is not possible. In addition, because it is common for patients with liver cancer to have additional medical problems such as cirrhosis, many patients whose cancers are considered resectableare excluded from surgery due to their overall health.
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 the cancer and the underlying liver disease. However, the number of liver donors is far smaller than the number of patients who may benefit from liver transplant and too often, patients who would otherwise be good candidates for liver transplantation are unable to receive them due to the lack of available organs.
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 have been investigated. These include: cryosurgery/ablation, radiofrequency ablation, ethanol injections, transarterial chemoembolization and radioembolization.
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 lesions less than 3 cm.
Ethanol injections involveinjecting ethanol (alcohol) directly into tumors using small needles. The high concentration of ethanol used in these injections can result in killing of the tumor. Only small tumors (less than 2 cm, no larger than 5 cm) can be treated in this manner; however, for 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 injection.
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 (Yttrium 90 microspheres) provides internal delivery of high dose radiation to the tumor area while sparing normal tissue. A catheter is threaded into the groin, passed into the liver, and the micropsheres are delivered to the tumor.
Another potential method of treating liver cancer is radiation therapy. The radiation comes in the form of high energy x-rays that are delivered to the patient only in the areas at highest risk for cancer. These x-rays are similar to those used for diagnostic x-rays, with much higherenergy. The high energy of x-rays in radiation therapy results in damage to the DNA of cells. Because cancer cells are not as efficientas normal, healthy cells at repairing DNA damage, radiation results in more damage to the cancer cells than to normal cells. Radiation therapy exploits this difference to treat cancers while relatively sparing normal tissue.
Although modern techniques allow radiation to be delivered in a very specific manner, a significant amount of normal liver is still treated when radiation therapy is used. Because of this, radiation is not routinely part of the treatment of liver cancers. Its use is most often reserved for cases in which other treatment options have failed, or when the liver cancer has spread outside of the body and is causing specific problems due to the location to which it has spread (for example, bone). A significant amount of research is currently underway that explores additional methods of improving the delivery of radiation to liver cancers. Avenues of research have included 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(an 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 multi-disciplinary approach to treatment.
Chemotherapy is a medication that is usually given intravenously 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. In general, use of chemotherapy in liver cancer has proven difficult because liver cancersarerelatively resistant to cytotoxic chemotherapy. 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 the 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, immediately after surgical resection of a tumor that has not spread beyond the liver. Despite the theoretical 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). Several different chemotherapy drugs have been studied for patients who have unresectable disease (not eligible for surgery), including 5-FU, oxaliplatin, doxorubicin, cisplatin, capecitabine and thalidomide. These agents have been used in combination, and as single agents, but they have not been found to be very effective in treating hepatocellular cancer. Bevacizumab, a monoclonal antibody that targets the tumor's blood supply, has also been studied and did not show significant effect on stopping the disease progression.
Newer treatments include the use of targeted therapies. Targeted therapies are medications that are designed to block specific steps in the reproduction/division of cancer cells. A medication called Sorafenib is the first targeted therapy to demonstrate an improvement in survival in patients with advanced HCC. Sorafenib targets two receptors important in cancer cell division and survival and is being studied in combination with chemotherapy and local therapies. In addition, there are ongoing studies evaluating the use of sorafenib after liver transplantation. Another type of targeted therapy, nivolumab, has recently been approved for the treatment of advanced liver cancer, for patients previously treated with Sorafenib. Other agents that target various proteins on the tumor cell are being investigated, including lenvatinib, linifanib, cabozantinib, and ramucirumab, which have shown varying improvement in response rates in recent investigational 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 because of the high rate of recurrence in patients who have been treated and because of the 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. Prompt evaluation and treatment of suspicious findings is critical.
Fear of recurrence, relationships and sexual health, 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 some15 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 Education resources and support services for liver disease.
Appendix: Complete Liver Cancer Staging
AJCC, Cancer Staging Manual, 8th Edition
Primary Tumor (T)
Primary tumor cannot be assessed
No evidence of primary tumor
Solitary tumor < 2cm or >2cm without vascular invasion
Solitary tumor < 2cm
Solitary tumor >2cm without vascular invasion
Solitary tumor >2cm with vascular invasion or multiple tumors none more than 5cm
Multiple tumors, at least one that is more than 5cm
Single tumor or multiple tumors of any size involving a major branch of the portal vein or hepatic vein or tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum
Regional Lymph Nodes (N)
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
Regional lymph node metastasis
Distant Metastasis (M)
No distant metastasis
Distant metastasis, microscopically confirmed
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.
Histologic Grade (G)
Grade cannot be assessed
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