Liver Cancer

The liver forms part of the gastrointestinal system, which is responsible for breaking down food into smaller parts that can be used by cells.  The liver is located in the abdomen, below the ribcage. It is a large organ with many different functions, including: 3

• Production and secretion of bile and bile salts to help digestion and absorption.
• Production of insulinA protein hormone secreted by the pancreas. Insulin controls glucose levels in the body by increasing uptake of glucose into cells of the body. Insulin also stimulates the formation of glycogen and alters fat and protein metabolism.-like growth factorA substance that stimulates cell division. Growth factors are usually small proteins or steroid hormones. They may be secreted by the same cells on which they act or by cells that reside in a different part of the body than the target cells. Some examples of growth factors include estrogen, a growth factor for breast cells, and VEGF, a growth factor that causes the development of blood vessels. Several different anti-cancer treatments are designed to inhibit the activity of growth factors. (IGF-I).
• Production of clotting factors.
• Release of glucose into the blood to provide energy for cells.
• Production of urea, a waste product.
• CholesterolA type of lipid, cholesterol is part of a group of molecules called steroids. Cholesterol is essential for the structure and function of our cellular membranes. Testosterone and estrogen are other steroids that are very similar to cholesterol in structure. production.

Behind the liver, there’s a small organ called the gallbladder, which function’s to store bile produced by the liver and empty it into the small intestine to aid digestion and absorption. 4

The large number of different cell types in the liver makes it vulnerable to the formation of more than one type of cancer. As with tumors that form in any other location, these can be either invasive (malignantA tumor that has invaded neighboring tissue.) or contained (benignA growth that does not leave its site of origin or invade surrounding tissue. Benign growths can get large and are capable of causing illness or even death, depending on the location of the growth. Technically, benign growths are not cancer.).5

Hepatocellular carcinomaCancer of epithelial cells, the cells that cover the outside and inside of body surfaces. This is the most common form of cancer. (HCC)
The most common type of liver cancer is hepatocellular carcinoma. HCC starts with an abnormal growth of a cell called hepatocytes (‘hepat’ and ‘hepato’ are derived from the Greek word for liver).  This is a liver-specific cell that is the start of the tumor. Most patients with this type of cancer are over 50 and it is more common in males than in females. Hepatocellular carcinoma can metastasizeThe movement of a cancer to a location outside its site of origin. The distant growths are termed metastases., and when it does, it frequently goes to nearby lymph nodesA grape-like cluster of lymphatic tissue. Lymph nodes (or lymph glands) filter the lymph fluid that flows through the lymphatic system. Lymph nodes collect fluid from discrete regions of the body and are often examined for the presence of metastasizing cancer cells. and to the lungs. 6

Cholangiocarcinoma
This kind of carcinoma, also known as bile duct cancer, comes from the tissues of the tubes that connect the liver to the gallbladder and the gallbladder to the small intestine (hepatic bile ducts). Cholangiocarcinoma can also come from the ducts located inside the liver (intrahepatic ducts).  Review the anatomy of these organs here. 

Most cholangiocarcinomas are adenocarcinomas (they form in glandular tissue) but they frequently grow slowly and don’t metastasize for long periods of time. Because the cancer has few specific symptoms and can be confused with other liver conditions (hepatitis or cirrhosis), it is difficult to detect early and is usually in advanced form when discovered. The average age of patients at diagnosis with cholangiocarcinoma is 65. 7

Hepatoblastoma
Hepatoblastoma characteristically develops in children; it is most frequently diagnosed in infants between 14 and 24 months and almost all patients are diagnosed by the age of 5. 8 Older children and adults can develop this carcinoma, but it is very rare. This type of cancer is the result of an uncontrolled proliferationRefers to cell division. The proliferation rate is an indicator of how quickly a tumor is growing. The proliferation rate may be represented as a percentage, showing what fraction of the cells are actively involved in the division process. (meaning that the cells that won't stop dividing) of undeveloped liver cells (hepatocytes). Hepatoblastoma is usually found in only one place (unifocal), it’s uncommon for it to metastasize. 9

Hepatitis C VirusThe smallest type of organism known. A single virus particle (called a virion) is much smaller than a cell. Viruses reproduce by invading cells and forcing the cells to make progeny virions. Viruses generally have specific host cells which they infect. Some virus types are associated with specific cancers and can convert normal cells into cancer cells. Examples of viruses associated with cancer are: papillomavirus-cervical cancer, hepatitis virus-liver cancer, Epstein-Barr virus-Burkitt's lymphoma. Virus-induced transformation of cells was one of the very first model systems for the study of cancer. Viruses have also been a key tool in the identification of many oncogenes. Because of their great ability to enter target cells viruses such as adenoviruses are being examined for their ability to deliver genes to cancer cells. (HCV):
For Western countries including the U.S., infection with hepatitis C is the leading cause of both hepatocellular carcinoma (HCC) and chronic liver disease. It is of special importance because unlike the hepatitis B virus, there is no vaccine available for the hepatitis C virus. 10

Excessive alcohol intake:
Alcohol liver disease is the second most common risk factor for HCC in the U.S., after infection with hepatitis C virus.11http://www.ncbi.nlm.nih.gov/pubmed/11088082?dopt=Abstract&holding=npg] [PUBMED]

Geography:
More than 80% of HCC cases appear in Eastern Asia or sub-Saharan Africa. North and South America, Northern Europe and Oceania have much lower incidence rates. 12

Ethnicity:
In the United States, HCC incidence rate of Asians is twice as high as that of African Americans and four times that of whites.12

Sex:
Males have a higher liver cancer rate than females. The difference in the male:female ratio is greatest among Europeans. The difference between the rates is likely caused by different exposure to risk factors including alcohol consumption, cigarettes, and infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). More on HBV and HCV here.12

Age:
In developed countries (including Canada and the United States) and most Asian populations, HCC is most likely to occur in people 75 years old and older. On the other hand, the peak age of African men with HCC is 60 and 65 years old and the number of individuals with HCC then decreases. The peak age for African women occurs between 65 and 70 years old and then decreases.12

Hepatitis B Virus (HBV):
Those who carry HBV have a 5 to 15 fold increased risk of developing HCC over the general population. Between 70 and 90% of HCCs related to the presence of HBV are diagnosed in patients that suffer from cirrhosis. Cirrhosis is advanced scarring on the liver caused by liver diseases (including hepatitis) and other conditions.

In places with high HCC incidence rates, HBV is usually transmitted from mother to child (vertical transmission), whereas in areas with low HCC incidence rates patients usually get infected with HBV through sexual and parenteral ways (horizontal transmission). 12

Obesity:
A 16-year period study in the United States showed a 5 fold increase in cancer mortality in people with great body mass index in contrast to those who had a normal body mass index. Liver cancer is frequently found in patients with metabolic disarrangements. 12

Diabetes Mellitus:
Many studies around the world have found a significant relationship between diabetes and the development of HCC. Between 10 and 20% of cirrhosis patients have overt diabetes and a higher percentage present impaired glucose tolerance. 12

Tobacco:
The association between smoking and HCC still is not yet clear. Studies have produced conflicting results, showing both negative and positive relationships. However, two studies focused on women both reported a positive association, so smoking may be a higher risk factor for women than men. 12

Exposure to aflotoxins:
Aflatoxins are a type of mycotoxin, toxic chemicals made by some types of fungi. Aflatoxin is produced by Aspergillus fungi when the fungus grows on improperly stored food products. Aflatoxins are capable of causing DNAAbbreviation for deoxyribonucleic acid. Composed of very long strings of nucleotides, which are abbreviated as A, C, G and T. DNA is the storage form of our genetic material. All of the instructions for the production of proteins are encoded in our DNA. mutations, including the tumor suppressorA gene that functions in the control of cell division. Tumor suppressors normally work to limit cell division and may be contrasted with oncogenes., TP53  (p53A tumor suppressor gene that is mutated in over 50% of cancers of all types. The p53 protein is a transcription factor that controls entry into the cell division cycle. Many signals about the health of a cell are relayed to the p53 protein. This results in a decision by the cell as to whether or not cell division should occur. If the cell is damaged and can not be repaired, the p53 protein is involved in triggering a chain of events that causes the cell to kill itself in a process termed apoptosis. Cells defective for p53 do not have these controls and tend to divide even when conditions are not favorable. Like all tumor suppressors, the p53 gene is normally involved in slowing or monitoring cell division.). Aflatoxins may be found in peanuts, tree nuts, corn, wheat and other grains, and oil seeds. 13, 10

Symptoms & Detection

Liver cancer generally does not have symptoms. Nonspecific symptoms that can be associated with HCC may include:
·         Yellowish color of the skin (Jaundice)
·         Inability to eat (Anorexia)
·         Weight Loss
·         Abdominal pain and/or swelling
A surveillance ultrasound is recommended every six months for individuals with a high risk of developing HHC.
In patients with liver cirrhosis, if the ultrasound reveals a suspicious liver lesionThis is a broadly used term in pathology and refers to any defined (localized) structural abnormality or injury. The word 'lesion' does not imply that something (i.e. a tumor) is necessarily serious or advanced., a CT or MRIAlso: nuclear magnetic resonance imaging (NMR). Magnetic Resonance Imaging is a non-invasive imaging procedure that utilizes strong magnets and radio waves to visualize tissues. Subtle differences in the ways that the tissues and organs absorb and reflect the waves enable the detection of many different disorders. can be used to determine if the abnormality (lesion) is HCC. If the patient has no underlying cirrhosis or if imaging results prove inconclusive a biopsyA medical procedure in which a sample of tissue is removed for examination. Biopsies can range from a small sample drawn into a needle to samples taken during more invasive surgery. can be used.

If there is suspicion that a patient may have liver cancer, a sample of tissue (biopsy) may be taken for examination. After a biopsy is taken, the physician who performed the biopsy sends the specimen to a pathologist. The pathologist examines the specimen at both the macroscopic (visible with the naked eye) and microscopic (requiring magnification) levels and then sends a pathology report to the physician. The report contains information about the tissue's appearance, cellular make up, and state of disease or normalcy. For more information about pathology reports, refer to the Diagnosis & Detection section.

A variety of staging systems have been used for liver cancer. T/N/M and the Barcelona Clinic Liver Cancer staging system (BCLC) are the most common.14

The BCLC uses a four-stage system:
A. Includes patients with asymptomatic early tumors  (meaning that they do not show symptoms)
B. Patients with asymptomatic multinodular HCC (still no symptoms, but now there's a handful of grapes versus only one grape like in stage A)
C. Patients with symptomatic tumors and/or invasive tumor pattern
D. End stage disease. Should only receive symptomatic treatment

The T/N/M system assigns a degree of severity based on size, location, and spread of the cancer in the body. Learn more about T/N/M staging.

TP53:
p53 is a tumor suppressor geneA stretch of DNA that leads to the production of an RNA. The RNA is produced during the process of transcription. This RNA can be used to guide the formation of a protein via translation or can be used directly in the cell. in charge of regulating cell division and apoptosisAlso called programmed cell death. Apoptosis is a natural process that occurs throughout the lives of almost all animals and plants. The death of the cells is a carefully controlled process that does not generate any inflammation.. About half of all human tumors have a mutation in the TP53 tumor suppressor gene. Several studies have reported that mutations in p53 have a critical role in the development of HCC.15
 

pRb:
pRb is a tumor suppressor gene. Together with TP53 it regulates cell division. the disruption of the pRb pathway in HCC is similar to that of other cancers. 15
 

RasA proto-oncogene that is found to be mutated in many different kinds of cancer. The ras protein is involved in transmitting signals through the cell that drive the cell into the division process.:
The human ras proteinOne of the four basic types of biomolecule. Proteins are polymers made up of strings of amino acids. Proteins serve many functions in organisms including transport of molecules, structure, cell adhesion and as signaling molecules such as hormones. Many transcription factors, including p53 and Rb are proteins. family is a family of proteins that drive cell division.
A recent study reported that some of the Ras family inhibitors are inactivated in human HCC, demonstrating the role of Ras pathway signals in liver cancer. 15
 

NOTCH 2:
The NOTCH family is involved in several cell functions, such as proliferation, differentiationThe maturation of a stem cell into a fully functional cell. Fully differentiated cells are often not able to divide and many cancers are thought to arise via mutations in the small number of stem cells that remain in the tissue. and cell death (apoptosis).16Hepatoblastoma can be the result of more than one type of translocation in the long arm (q) of chromosomeA long DNA molecule containing genetic information (genes). Humans have 46 chromosomes. One set of 23 is inherited from each parent. A full set of chromosomes is present in the nucleus of each human cell. 1.  The NOTCH 2 protein has been found to delay the maturation of hepatoblasts during liver development; its expression is associated to the differentiation of the hepatoblasts into hepatocytes and biliary cells. It is thought that NOTCH 2 contributes to hepatoblastoma by keeping a population of hepatoblasts from differentiating.17

Treatment options for HCC depend on how well the liver is functioning, the tumor stage, and the physical status of the patient.
As our focus is on the biology of the cancers and their treatments, we do not give detailed treatment guidelines. Instead, we link to organizations in the U.S. that generate the treatment guidelines.

Learn about treatment guidelines for HCC from the National Comprehensive Cancer Network (NCCN).

A study from 2011 suggests that liver cancer may arise from a type of cancer stem cellCells capable of developing into more than one cell type. All of the cells in a human body come from the division and subsequent differentiation of a single cell, formed from the fusion of an egg and sperm. This original cell has the capability to form any cell type and is called totipotent. As tissues develop the cells lose the ability to form all other tissues, and become 'committed' to forming only one or a few cell types. These stem cells are called pluripotent. An example are bone marrow cells that form many different kinds of blood cells. Stem cell replacement allows for the pluripotent stem cells in bone marrow to be replaced after high doses of chemotherapy. Many fully differentiated cells are not capable of cell division and are replaced when they die by the division of stem cells in that tissue. Many forms of cancer are thought to be the result of abnormal division of stem cells. that is resistant to chemotherapyTreatment of cancer patients with anticancer drugs. Commonly called 'chemo'. These drugs work by attacking cell growth or division. Often these agents are used in combination to take advantage of their different modes of attack on cell division. and has the ability to metastasize to the rest of the body.  These capabilities make it possible for liver cancer to recur after it is surgically removed. 18

Learn more about the treatment for liver cancer at the Winship Cancer Institute of Emory University.
For more information about how these and other cancer treatments work, refer to the Cancer Treatments section.

Information about clinical trials:
. General clinical trial information from CancerQuest
·Click here for information about clinical trials at the Winship Cancer Institute of Emory University. Click here for information about clinical trials from the National Cancer Institute.
·Click here for information about clinical trials from Georgia Clinical Trials Online.
 

Introduction

·         Liver cancer is the fifth major cause of cancer-related deaths in the U.S.

·         In the U.S., this cancer is the fifth most common cancer in men and seventh in women.

Types of Liver Cancer

·         Hepatocellular carcinoma (HCC) is the most common form, patients are usually over 50.

·         Cholangiocarcinoma arises from the connective tissues of the bile ducts.

·         Hepatoblastoma characteristically develops in children.

Risk Factors

·         Infection with hepatitis C is the leading cause of HCC in Western countries.

·         Alcohol-related liver disease is the second most common risk factor for HCC in the U.S

·         More than 80% of HCC cases appear in Eastern Asia or sub-Saharan Africa

·         Males have a higher liver cancer rate than females, presumably due to different exposure to risk factors.

·         Liver cancer risk increases with age.

·         Those who are infected with the Hepatitis B virus (HBV) have a 5 to 15 fold increased risk of developing HCC over the general population.

·         Liver cancer is frequently found in patients with metabolic disorders.

o   A significant relationship has been found between diabetes and HCC.

Symptoms and Detection

·         Liver cancer rarely presents with specific symptoms.

·         Nonspecific symptoms that can be associated with HCC include jaundice (yellow coloring), anorexia, weight loss, and abdominal pain.

Staging and Pathology Report

·        A sample of liver tissue is examined micro- and macroscopically in order to create a pathology report.

·        The Barcelona Clinic Liver Cancer (BCLC) system has four-stages.

·         The T/N/M system assigns a degree of severity based on size, location, and spread of the cancer in the body

Tumor Biology

·         Mutations in p53 have a critical role in the development of HCC

·         The disruption of the pRb pathway seen in HCC is similar to that of other cancers.

·         NOTCH 2 contributes to hepatoblastoma by preventing a population of hepatoblasts from differentiating.

Treatment

·         Treatment options for HCC depend on how well the liver is functioning, the tumor stage, and the physical status of the patient.

Learn more about liver cancer or make an appointment at the Winship Cancer Institute of Emory University.