Liver Cancer
by V. Barbounis, M.D., Medical Oncologist

Introduction

Liver cancer (hepatocellular carcinoma or hepatoma) is a cancer arising from the liver. The majority of primary liver cancers (over 90%-95%) arise from liver cells. Liver cancer is the 3rd most common cancer in the world; this form of cancer can be aggressive because the majority of patients with this disease often die within one year.

Many patients with liver cancer do not develop symptoms until they have advanced stages of the tumor. When the patient recognizes that develop symptoms, the prognosis is poor. However, the natural history of liver cancer is quite variable and depends on various factors.

 

Etiology

The most common implicated factors for hepatocellular cancer development are chronic infection from hepatitis B and C, liver scarring (cirrhosis), high alcohol consumption, the chemical agent aflatoxin, and less frequently the use of some drugs or chemicals. All of these diseases cause continual damage to the liver, which can result in severe cirrhosis that can subsequently lead to cancer

 

Hepatitis B and C infection

The role of hepatitis B virus (HBV) infection as causal factor for liver cancer is well established. The frequency of liver cancer correlates with the frequency of chronic hepatitis B virus infection. In a study from Taiwan the investigators found that the risk of developing liver cancer was 200 times higher among persons who had chronic hepatitis B virus as compared to those without chronic hepatitis B virus infection.

The postulated mechanism is that specific regions of the hepatitis B virus genome enter the genetic material of the liver cells causing them malignancy.

Hepatitis C virus (HCV) infection is also associated with the development of liver cancer. Hepatocellular cancer occurred about 8-10 years after the development of cirrhosis in patients with hepatitis C.

The way in which hepatitis C virus causes hepatocellular cancer is not well understood. However, the presence of hepatitis virus C in the liver is absolutely necessary for the development of liver cancer from long standing hepatitis C virus infection. Cirrhosis from alcohol consumption is the most common factor associated with hepatocellular cancer.

Aflatoxin, a product of Aspergillus, which is found in food is the most potent liver cancer-forming chemical agent. Aflatoxin is found in bread, peanuts, rice, soybeans and corn. The underlying mechanism is the set of alterations produced by the aflatoxin to the p53 gene, nullifying the gene's suppressing functions. Hemochromatosis, a disorder in which there is excess iron stored in the liver, is a causative factor for developing cirrhosis and subsequently, hepatocellular carcinoma.

Diabetes and obesity are producing fatty liver disease which can damage liver tissues and may lead to cirrhosis, increasing the risk of liver cancer.

 

Liver scarring (cirrhosis)

People with cirrhosis are at an increased risk of developing liver cancer. However the various forms of liver cirrhosis are not associated with the development of hepatocellular carcinoma.

 

Epidemiology

In 2000, it was estimated that there were about 564,000 new cases of hepatocellular carcinoma worldwide. The vast majority of these cases are found in China, Korea, Japan and Taiwan. The frequency of liver cancer in Southeast Asia is greater than 100 in 100,000 people. In North America and Europe the frequency is much lower, approximately 5/100,000 of the population. This difference is due to liver cancer being closely associated to chronic hepatitis B infection.

It takes a long time of liver damage before the cancer become obvious. Men are much more likely than women to have liver cancer. It is noticeable that about 25%of patients with liver cancer have no obvious risk factors.

 

Clinical Symptoms

The clinical presentation of liver cancer varies. The cancer usually reaches an advanced stage and causes various symptoms rapidly, before it gets diagnosed. There are no specific symptoms of liver cancer. The most common symptoms, although nonspecific, are the abdominal pain and/or the unexplained weight loss or unexplained fevers. The appearance of ascites (fluids in the abdomen), jaundice (bile in the blood), and muscle wasting (atrophy of muscles) is also associated with liver cancer. Esophageal varices (dilatation of veins) are also a consequence of liver cancer and the underlying cirrhosis.

The most common finding during physical examination is the enlarged, tender liver. In advanced disease, the cancer can spread to neighboring tissues, or elsewhere in the body. Depending on its location the tumor will give a variety of symptoms and signs.

 

Diagnosis

Blood tests, imaging studies, and liver biopsy or aspiration may be used to diagnose liver cancer.

 

Blood tests

Since most patients with liver cancer have associated liver disease, their liver blood tests may be abnormal from the very beginning. 

The most valuable biochemical blood test is alpha-fetoprotein (AFP), which is a protein normally produced by the immature liver cells in the fetus. In adults, high blood levels (over 500 ng/ml) of AFP are suggestive of liver cancer. Generally, the normal levels of AFP are below 10 ng/ml. The sensitivity of AFP for liver cancer is about 60%, however, a normal AFP does not exclude liver cancer.

 

Imaging studies

Imaging studies play a very important role in the diagnosis of liver cancer. They give information about the size of the tumor, the number of tumors, and its extension outside of the liver. The information regarding the involvement of major blood vessels is also very important.

Ultrasound examination is usually the first study ordered because it is cheap and simple, and it is very sensitive to reveal a lesion but not very specific. Furthermore, ultrasound has the advantage of not requiring intravenous contrast media or radiation.

Computerized axial tomography (CT scan) is the most common study used for the recognition of tumors in the liver. The CT scan requires oral and intravenous contrast media. The radiologists use a specific protocol that determines how the contrast is infused, and how it is washed out in the various lesions.

Imaging with magnetic resonance (MRI) can provide liver images with higher accuracy than the previous described methods. The MRI is able to reconstruct images of the biliary tree, of the arteries and veins of the liver. Sometimes it is necessary to use intravenous contrast media. MRI is able to reveal lesions smaller than those that can be seen on a CT scan.

Angiography and PET/CT (positron emission tomography) scans are two other methods of liver imaging. However, they are not used very often, because they do not add more information to the previous three methods.

 

Liver biopsy

A definitive diagnosis of liver cancer is always based on histological examination. However, there are many diagnostic problems to discern the hepatocellular carcinoma from other adenocarcinomas developed outside of the liver or from the healthy parenchyma. Therefore, it is important that an expert liver pathologist review the available tissue in questionable cases. New advances in immunohistochemistry have enabled us to distinguish liver cancer from other forms of cancer, or from a normal liver.

One can obtain tissue either with fine needle aspiration or with a core biopsy. These biopsies are performed by radiologists, under ultrasound or CT scan guidance. The most common risk of these procedures is bleeding, however sometimes new foci of tumor can be seeded along the needle track. The fine needle aspiration procedure is not recommended because only a cluster of cells is available for evaluation, while tissue obtained with a core biopsy needle is usually enough for a definitive diagnosis.

If a patient has a risk factor for liver cancer and a significantly elevated serum alpha-fetoprotein, the diagnosis of liver cancer is certain and a liver biopsy is not necessary. On the other hand there are situations where a biopsy may be considered as necessary: to characterize a possible tumor seen by imaging methods in the absence of risk factors, and to determine the extent of disease when there are multiple tumors in the liver.

 

Staging

The stage of a cancer indicates the extension of the tumor. It is extremely important because it influences the treatment decisions. The stage of cancer depends on the size of the tumor, whether the cancer has grown into blood vessels and whether cancer has spread to lymph nodes or other organs in the body

  1. Stage 1There is a single tumor and the cancer has not spread to the blood vessels, lymph nodes or any other part of the body.
  2. Stage 2There is a single tumor that has grown into blood vessels of the liver or several tumors that are less than 5cm but have not grown into the blood vessels
  3. Stage 3:
  • Stage 3A: There is more than one tumor, and at least 1 of them is larger than 5cm. No spread to the lymph nodes or any other part of the body are evident.
  • Stage 3B: Tumor has invaded into one of the main blood vessels of the liver . No spread into the lymph nodes, without distant metastasis.
  • Stage 3C: The tumor has infiltrated the organs near the liver or there are deposits on the visceral peritoneum . There is no lymph nodes involvement or distant metastasis.
  1. Stage 4
  • Stage 4A: The cancer may have grown into blood vessels or the organs around the liver. It has spread to lymph nodes but not to distant organs.
  • Stage 4B: The tumor may have infiltrated the blood vessels. It may or may not have spread into lymph nodes, but has spread to other organs such the lungs or bones.

 

Pathology

Within the group of primary liver cancers, there are 4 main categories. These are Hepatocellular carcinoma (HCC), cholangiocarcinoma, angiosarcoma, and hepatoblastoma..

This analysis will focus on HCC and cholangiocarcinoma.

Hepatocellular carcinoma (HCC)

Other name of this entity is hepatoma or HCC. It is the most common type of primary liver cancer. It develops from the cells which called hepatocytes. It is more common in men than in women, and in younger people.

Fibrolamellar carcinoma

Fibrolamellar carcinoma is a rare sub-type of hepatocellular cancer (HCC). Fibrolamellar carcinoma is common in younger people without cirrhosis or infection with hepatitis B or C. It is very interesting that patients with fibrolamellar carcinomas do not have elevated levels of serum alpha fetoprotein. Surgery is the main form of treatment. The fibrolamellar carcinoma, when totally excised, has a better prognosis than HCC.

Cholangiocarcinoma

It is another hepatic cancer subtype derived from the epithelium cells lining the bile ducts. There are two main subtypes: intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma.

 

Treatment Strategies

Although Hepatocellular carcinoma is a manageable cancer, it is not curable. The decision for the optimal treatment is based on the general condition of the patient, and the availability of the various treatment modalities.  The treatment strategy comprises the resection of the lesion (if it is small) or the excision of the lesions if they are confined to one lobe.

Unfortunately, many patients with liver cancer are suffering from cirrhosis and they are not candidates for liver resection. In a small proportion of patients, liver transplantation is the only option for treatment, but worldwide liver resources for transplantation are very limited.  

 

Chemotherapy

The most active systemic chemotherapeutic agents are doxorubicin and 5-fluorouracil (5 FU).

There are two problems with the implementation of this treatment: it is toxic and not very successful. New agents such as cisplatin, gemcitabine, or oxaliplatin are moderately active and are effective to some extent in some patients. Octreotide has shown in one study to slow the progression of liver cancer, but no other studies have confirmed these results.

New drugs

One of the most important advances in the battle against liver cancer has been the understanding of its genetic profile. Angiogenesis is a very important part of the tumor growth. Targeting this process facilitates the ability to destroy the tumor cells, and to depress the tumor proliferation.

The new agent sorafenib blocks several parts of the angiogenesis pathway. Initial studies have shown that when the drug is given for advanced liver cancer, it offers a significant life advantage in comparison to those taking placebo. Although the difference was not very long (only three months), this is the first study that shows a therapeutic improvement. Sorafenib is approved by the U.S. FDA to treat liver cancer.

Chemoembolization

Chemoembolization (sometimes referred to as Transcatheter Arterial Chemoembolization or TACE) is a technique that delivers chemotherapy locally to the tumor and has the advantage to stop the tumor blood perfusion from the branches of hepatic artery. This procedure is similar to intra-arterial infusion of chemotherapy and is accomplished by blocking the small blood vessels with a gel foam. Thus, this technique deprives the tumor of the necessary blood supply, exposing the tumor cells to high concentration of chemotherapeutic drugs which can result in the damage of the tumor cells.

 

Radiotherapy

Radionuclides treatment is the administration of conjugated radioactive isotopes to tiny beads directly into the blood vessels of the tumor. These radioactive particles are effective in killing tumor cells in their vicinity. They have fewer complications than chemoembolization, while their effectiveness is comparable to it.

Radiofrequency ablation

Radiofrequency ablation (RFA) is the treatment of choice for tumor destruction. The procedure can be performed laparoscopically or using ultrasound or CT guidance. In this procedure, heat is generated by sending radio waves to metal electrodes introduced to liver tumors. The heat destroys the tissue by coagulative necrosis, and the duration of the procedure is 10-15 minutes. The appropriate size of the  tumor for RFA is between 2-5 cm. Larger tumors may require more than one introduction, nevertheless the response is not satisfactory as in the case of small tumors (around 2 cm).

Cryoablation

Cryoablation is similar to RFA procedure but instead of using heat, cryoablation uses liquid nitrogen to freeze the tumor and thus to kill the cancer cells. It has the advantage that it can be used in some areas where heat is dangerous to damage adjacent organs but it is similarly effective as radiofrequency ablation

X-knife

Stereotactic radiosurgery is a relatively new technique where radiation is administered with extreme accuracy directly to the tumor. The method uses computer planning and CT scans to construct the treatment plan and then directs the radiation beam precisely on the tumor, thus sparing the normal liver from cumulative high doses that the normal liver cannot afford. X-knife is very effective against solitary tumors.

 

Surgery

Surgical options are limited to individuals whose tumors are less than 5 cm and confined to the liver, with no invasion of the blood vessels. For patients whose tumors are fully removed, the five-year survival rate is up to 60%. Unfortunately many of these patients will experience a recurrence of liver cancer elsewhere in the liver.

 

Genetics

People with a first-degree family history of liver cancer were approximately four times more likely to develop liver cancer than patients without family history. This increased risk was observed in the group of people not affected by viral hepatitis. 

Hemochromatosis is a disease in which the body stores excessive amounts of iron. The majority of this iron is placed in the liver. Hereditary hemochromatosis, occurs when the patient inherits a specific genetic mutation from his parents. People with hereditary hemochromatosis have an increased risk of developing hepatocellular carcinoma.

 

Early Detection

The progress in liver cancer screening has been conjugated with earlier detection and probably higher cure rates. However, there are no conclusive data that screening reduces the risk of death from liver cancer. It is sensible for individuals at high risk for liver cancer to undergo regular screening (every 6-12 months) with ultrasound of the liver and serum alpha-fetoprotein measurement.

Alpha-fetoprotein is associated with elevated serum levels in liver cancer. Thus the measurement of this protein may be used as a screening method for liver cancer.

 

Screening

There is no cost-effective way of screening for liver cancer. Alpha-fetoprotein is not sensitive enough for the small tumors, and also it is not very specific. Furthermore, ultrasound is cheap but not very objective.

Patients with cirrhosis, caused by hepatitis B or C, hemochromatosis, and alcohol, should be screened every 6-12 months with alpha-fetoprotein and ultrasound or MRI.

 

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