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2003 Meet the Expert: The Virus-Cancer Link: Examining the Role of Viruses in the Development of Cancer
Introduction
Improving cancer care and prevention are high priorities for the American Society of Clinical Oncology (ASCO), the leading society of medical professionals who treat people with cancer. For that reason, ASCO has developed patient resources, such as the Cancer Advances series, to help consumers become better educated about various aspects of cancer, including its prevention, screening, diagnosis, treatment, and care.
This issue of Cancer Advances focuses specifically on the relationship between viruses and cancers. More than a dozen viruses have been associated with specific types of cancer. Researchers are still learning how a cell that is infected with a virus becomes a cancer cell and continue to make discoveries that lead to better methods to prevent, diagnose, and treat viral cancers.
According to Bruce E. Johnson, MD, Director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute in Boston, Mass, and Chair of ASCO's Cancer Communications Committee, this topic is becoming more important as an increasing number of viruses and infectious agents that have a direct link to cancer are being identified.
The information contained in this publication was presented at an ASCO Meet the Experts session held in New York City in December 2003. This event covered information about the incidence, risk, infection process, prevention, screening, and treatment of the following cancers that are linked to viruses or bacteria.- Hepatitis B and C and liver cancer
- Cancers associated with the human papilloma virus
- Helicobacter pylori and stomach cancer
- Viruses associated with leukemia and lymphoma
- Viruses associated with Kaposi's sarcoma
The information contained in this publication is not intended as medical advice or as a substitute for a doctor's opinion. ASCO does not endorse any products or companies mentioned in this publication.
About Viruses
Viruses cause infections that can lead to disease. A virus is a set of genes surrounded by a coat or shell of protein. Viruses are tiny; they can only be seen through powerful, specialized microscopes. "Viruses can contain different amounts of genetic information, anywhere from five genes in a very, very small virus or up to 100 genes in a large herpesvirus. As a reference, humans have probably 35,000 or more genes," explained James J. Goedert, MD, Chief of the Viral Epidemiology Branch and Senior Investigator at the National Cancer Institute in Bethesda, Md.
Viruses cannot make more viruses (replicate) by themselves. They need to first get inside (infect) a living cell, such as those in animals, humans, or bacteria (a host). During replication, the virus creates copies of itself called virions. The infectious virions are released from the cell, typically killing the host cell in a process called lysis. The virions can now infect nearby cells and spread to other people.
Viruses can also be inactive (latent) for many years, meaning they do not cause any symptoms right away. Sometimes these viruses are multiplying, but remain hidden from the body's immune system. Often, latent viruses require additional factors to become "reactivated" and cause infection.
Scientists classify viruses as DNA (deoxyribonucleic acid) viruses or RNA (ribonucleic acid) viruses. DNA and RNA are similar chemicals that store genetic material.
Viruses and Cancer
Viruses were first recognized as disease-causing agents at the close of the nineteenth century. Additional discoveries in the twentieth century showed that viruses could lead to a number of cancers in animals and humans.
"There are several known human cancer-associated viruses," said Dr. Goedert. "The first viruses associated with cancer were discovered in 1964—Epstein-Barr virus (EBV) was one, and the hepatitis B virus (HBV) was then found in 1970."
Established Viral Causes of Cancer:- HBV and hepatitis C virus (HCV) and liver cancer
- Human papillomavirus (HPV) and anal, cervical, and head and neck cancers
- Human T cell leukemia virus type 1 (HTLV-1) and adult T cell leukemia and lymphoma (ATLL)
- Human herpesvirus-8 (HHV-8) and Kaposi's sarcoma (KS)
- EBV and Hodgkin lymphoma
Potential Virus-Cancer Links Currently Being Studied:- HCV and some types of non-Hodgkin lymphoma
- Polyomaviruses in multiple cancers
- JC Virus–brain and colon cancers
- BK Virus–brain cancer
- SV40 Virus–brain, pituitary, bone, and thyroid cancer, non-Hodgkin lymphoma, and mesothelioma (a form of lung cancer)
- Breast cancer and a human virus similar to the mouse mammary tumor virus (MMTV)
Identifying, treating, and even possibly preventing cancers caused by viruses is an ongoing challenge because each virus causes cancer through a different process. In addition, some viruses cause cancer indirectly. For example, because HIV reduces the ability of the immune system to protect against illness, people infected with HIV are less able to fight off other infections that lead to cancer.
Prevention, Screening, and Treatment
Viruses that cause cancer are a natural target for prevention and screening efforts, which include the following strategies:- Stopping the spread of the virus
- Preventing infection in the first place, such as vaccines for hepatitis B
- Screening for the virus, which is beginning for HPV and cervical cancer
Doctors also hope that treating a viral infection will also treat the cancer. For example, certain therapies have been proven to reduce the number of Kaposi's sarcoma and non-Hodgkin lymphoma cases among people with acquired immune deficiency syndrome (AIDS).
According to Dr. Goedert, understanding the relationships among viral infection, immunity, and the genetics will help doctors understand more about the viral causes of cancer, and how to develop effective early diagnosis and prevention methods. And, developing other safe and effective therapies that target viruses will help lower the number of cancers that are associated with viruses.
Last Updated: September 27, 2004
The Viral Link to Leukemia and Lymphoma
Leukemia and lymphoma are cancers arising in blood-forming cells that affect the way the body makes blood and fights diseases. Two viruses that are linked to these cancers include the human T cell leukemia virus type 1 (HTLV-1) and the Epstein-Barr virus (EBV).
The HTLV-1 link to Adult T cell Leukemia and Lymphoma (ATLL)
HTLV-1 belongs to a group of viruses known as retroviruses. Unlike other viruses, HTLV-1 does not immediately destroy the cell during infection. Instead, this virus can remain silent for as long as 30 to 50 years. Francine M. Foss, MD, Director of Lymphoma and Experimental Therapeutics Service at Tufts-New England Medical Center in Boston, Mass, said that HTLV-1 is very good at hiding from the body's immune system, which allows the infection to develop.
Most people infected with HTLV-1 remain healthy. However, about 3% to 5% of the infected people eventually develop acute T cell leukemia and lymphoma (ATLL), a rare and fast-growing cancer of the blood. Other factors that contribute to the development of this cancer are not yet known. Because the virus has the ability to remain inactive for such a long time, ATLL and other diseases associated with HTLV-1 tend to occur in middle age.
There are two forms of ATLL: lower-risk (indolent) and higher-risk disease. Chronic ATLL and smoldering ATLL are examples of indolent disease, where the cancer cells grow slowly. Eventually, the indolent form of ATLL changes into the higher-risk, acute form of the cancer.
In acute ATLL and lymphoma-type ATLL, the cancer cells grow rapidly and disease develops quickly. Approximately 60% of people infected with HTLV-1 have acute ATLL, which is the most severe form of disease, said Dr. Foss. People with acute ATLL have a suppressed immune system, which means their bodies cannot fight infections very well. As a result, they often develop infections, such as pneumonia, which can be fatal.
Symptoms of ATLL are listed below:
- Swollen lymph nodes
- Swelling in the liver and spleen
- Lesions (areas of abnormal tissue) on the skin or bone
- Abdominal pain and diarrhea (if ATLL cells have moved into the digestive tract)
- Respiratory complications (if ATLL cells are in the lungs)
- Neurologic disorders (if the virus has infected brain tissue)
- Infections, in addition to HTLV-1
Incidence and Risk
Approximately 15 to 20 million people worldwide are infected with HTLV-1. The virus is widespread in southwest Japan, South America, the Caribbean Basin, and parts of Central Africa. The virus is also common in parts of the Middle East, Australia, and the South Pacific. However, recent immigration from these countries to the United States and Western Europe is changing this distribution.
HTLV-1 is transmitted by blood, breast milk, or through sexual intercourse. However, routine screening of donated blood for the presence of HTLV-1 has eliminated blood transfusion as a likely mode of transmission in most of the developed world. Users of illegal, intravenous drugs face a high risk of developing HTLV-1 infections due to sharing infected needles.
In addition, women appear to have a higher risk of being infected with HTLV-1. "The virus seems to be clustered in families and especially in women, suggesting that the transmission occurs more frequently from men to women and from women to children than it does from women to men," said Dr. Foss. "Some studies have even suggested that women are more than 100 times more likely to contract the disease from a male partner than the reverse."
Treatment
ATLL is a difficult cancer to treat. Treatment with two or more chemotherapy drugs is the most common approach. Although this therapy can reduce the size of the tumor, it's very difficult to control the disease, even with the most aggressive chemotherapeutic regimens, said Dr. Foss.
One effective chemotherapy combination is CHOP: cyclophosphamide (Cytoxan, Neosar), doxorubicin (Adriamycin), vincristine (Oncovin), and prednisone. Newer combination therapies include EPOCH (etoposide [VePesid], prednisone, vincristine, cyclophosphamide, and doxorubicin) and hyper-CVAD (cyclophosphamide, doxorubicin, vincristine, and dexamethasone).
"Over the last five years, researchers have looked for more novel approaches for this disease," said Dr. Foss. Those include trying to attack the virus using antiretroviral therapies, such as zidovudine (Retrovir or AZT), one of the first successful HIV therapies. It was not successful alone, but combined with the antiviral drug interferon, it has shown some potential to treat a less severe form of ATLL. Other new drugs undergoing study include arsenic trioxide (Trisenox), bortezomib (Velcade), arsenic trioxide and Denileukin diftitox (Ontak).
The EBV Link to Lymphoma
EBV is one of the most common viruses infecting humans. In fact, most people become infected with EBV at some point during their lives. EBV is transmitted by saliva and is often inactive. Infection can occur in childhood, even as early as infancy; however, it is rarely harmful and does not occur as often in children in the United States and other developed countries. When adolescents or young adults are infected, it causes mononucleosis 35% to 50% of the time.
EBV is a DNA virus that affects B cells, a type of white blood cell that helps create antibodies to fight infection. EBV has been linked with a fast-growing lymphoma called Burkitt's lymphoma. Although this cancer is rare in most areas of the world, it is one of the most common childhood cancers in central Africa. In addition, a number of studies suggest that EBV may also be linked to Hodgkin lymphoma, a cancer of the lymph system.
Incidence and Risk
The incidence of EBV-related Hodgkin lymphoma is increasing, primarily because there is a growing population whose immune systems are weakened, either from infection with HIV or drugs given after an organ transplant to prevent organ rejection. Both of these conditions make people more likely to get EBV because their bodies are less able to fight infection.
On average, lymphomas usually appear within the first one-to-two years after transplantation. All transplant patients are at risk, although the cancer occurs in up to 20% of people who received lung transplants. The most frequent symptoms of lymphoma experienced by transplant patients include fever and the swelling of the lymph nodes, liver, and spleen.
Lowering the dose of powerful drugs that slow down the immune system is one approach that seems to help organ transplant patients. In fact, some liver transplant recipients have seen their cancer completely disappear by reducing the amount of these drugs. If researchers can come up with better ways to prevent the body from rejecting transplanted organs without the use of strong drugs that slow down the immune system, there would fewer new cases of this cancer, said Dr. Foss.
Treatment
Hodgkin lymphoma can be treated with chemotherapy and radiation, and doctors are testing newer treatments. For example, one approach is to use antiretroviral drugs, such as ganciclovir (Cytovene), acyclovir (Zovirax), and foscarnet (Foscavir).
It would be best if we could develop treatments that target the virus, said Dr. Foss. She noted that there is a clinical trial underway that, if successful, could have a great impact on combating EBV-related cancers in organ transplant recipients.
Last Updated: September 27, 2004
Cancers Associated With Human Papillomavirus
Cervical, anal, and head and neck cancers are directly linked to the human papillomavirus (HPV), the most common sexually transmitted infection in the United States. There are more than 130 strains (types) of HPV, which are divided into two categories—mucosal types, which primarily infect the sex organs (genital tract), and cutaneous, which infect the skin.
The skin-related virus is common and causes warts on the hands, arms, legs, and feet. It is usually easy to treat, harmless, and not cancerous. Genital HPVs are primarily transmitted by sexual contact, including sexual intercourse, oral sex, and anal sex. Some strains of HPV are high risk, meaning they have been linked directly to cancer. There are 15 high-risk strains of HPV, including HPV-16 and HPV-18, which have the highest risk of developing cancer. In contrast, HPV-6 and HPV-11 are low risk strains and do not usually cause cancer.
Incidence and Risk
"HPV probably accounts for about one-third of the cancers that are known to be related to infections," said Maura L. Gillison, MD, PhD, Assistant Professor of Oncology at the Johns Hopkins School of Medicine in Baltimore, Md. These cancer types include the following:
- Cervical cancer
- Cancers of the head and neck, especially the tonsils
- Cancer of the mouth and larynx
- Cancers of the vulva, penis, and anal canal
"The incidence of cervical cancer in the United States has declined dramatically because of effective screening programs," said Dr. Gillison. "On the other hand, cancers of the anal canal and tonsils have dramatically increased since the 1960s. Nearly 70% of tonsil cancers are related to HPV infection."
Sexual behavior is the single greatest risk factor for HPV. Other risk factors include the following:
- The number of lifetime sexual partners
- An early age at first intercourse
- Unsafe behavior of a sexual partner
- A previous genital herpes infection or a previous HPV-related cancer
"The average woman who is infected with HPV clears her body of the infection over a period of eight to 12 months," said Dr. Gillison. "Individuals who don't clear it are considered to have a persistent (lasting) infection," she added, "one that is detected on more than two Pap smears, six months apart. A persistent infection is a risk factor for developing cancer."
Risk factors for developing HPV-associated cancers include the following:
- A weakened immune system, such as people infected with the human immunodeficiency virus (HIV) or those who have had an organ transplant
- Smoking, because nicotine can weaken the immune system
- The type of HPV
- A history of genital herpes or other sexually-transmitted disease
- A persistent (lasting) HPV infection
Prevention, Screening, and Treatment
Avoiding high-risk behaviors can prevent most HPV-related cancers. Pap tests and cervical exams are good ways to identify precancerous and cancerous cervical conditions caused by HPV.
"There have been a lot of developments in terms of screening, detection, and prevention," said Dr. Gillison, "but the single most important research initiative is the development of a vaccine for HPV-16." The vaccine is currently being tested. The hope for this or future vaccines, Dr. Gillison said, is to go a step further by counteracting more than just the HPV-16 strain. If a vaccine is able to trigger the development of antibodies against all cancer-related HPV infections, it will go a long way toward preventing the hundreds of thousands of HPV-related cancers that occur each year, she concluded.
The Virus-Cancer link
Because infections with high-risk viruses are more likely to lead to cancer, doctors are studying what makes them high risk, and how they can turn a healthy cell into a cancerous one. For example, in cervical cancer, the cancer-causing types of HPV produce two proteins called E6 and E7, which can turn a normal cell into a cancerous one by causing the cell to grow uncontrollably. The uncontrolled growth eventually leads to a tumor.
The infection of a cell by a high-risk virus like HPV-16 destroys two incredibly important genes that would normally lower the risk of developing cancer, said Dr. Gillison. "As a consequence of that action, there is a loss of cell control that eventually leads to cell death. This process contributes to how HPV causes cancers to progress."
Last Updated: September 27, 2004
Hepatitis B and C Viruses and Liver Cancer
Hepatocellular carcinoma (HCC) is the most common type of liver cancer in the world, with nearly one million cases each year. Usually less than 5% of people diagnosed with the disease live beyond five years.
Liver cancer is four times as common in men than women. HCC is 10 times more common in developing countries, particularly in Africa and Asia, than in the United States, where it is relatively rare. However, HCC is on the rise in the United States.
There was a 71% increase in HCC in the United States from 1975 to 1995, which led to a 45% increase in deaths between 1991 and 1995. "Although this increase is affecting all ethnic groups and most age groups, white men 45 to 54 years of age had the most rapid increase," said Andrew X. Zhu, MD, PhD, Assistant Physician, Massachusetts General Hospital in Boston. "This trend is likely to continue over the next 10 to 20 years, especially in white, middle-aged men."
There are five known types of hepatitis viruses, but only hepatitis B virus (HBV) and hepatitis C virus (HCV) have been linked to liver cancer. HBV and HCV are two different viruses that cause similar problems in the liver, including chronic infection, cirrhosis, cancer, and liver failure. In fact, the word "hepatitis" means "inflammation of the liver." Doctors suspect that chronic (long-term) HCV infection is the reason for the increase in new cases of HCC mentioned above.
Incidence and Risk
According to the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC), more than 350 million people worldwide are chronically infected with HBV, including 1.25 million in the United States. In countries where HBV is widespread, 80% of liver cancers are linked to the virus.
HCV is not as common. About 170 million people worldwide and close to 4 million in the United States are infected. HCV is very common in Egypt and Mongolia, but the patterns of infection can change quickly if risk factors are not well managed, said Dr. Zhu. "If blood product screening is not implemented very vigorously, we may see the rising incidence of HCV-related liver cancer in China, for example, over the next two to three decades."
Both HBV and HCV are spread through blood transfusions, contaminated needles from drug users, and unprotected sexual intercourse with infected partners. In addition, mothers with HBV can pass it to their children at birth or in early infancy, which is common in areas like Asia and Africa. HCV can also be passed from mother to child, but does not occur as frequently as it does in HBV.
"As an example of how strong the risks of transmission are from blood transfusion," explained Dr. Zhu, "it occurs once in every 60,000 transfusions with HBV and once in every 100,000 for HCV. This is five times more than the risks associated with contracting HIV by blood transfusion, which occurs probably once in every 500,000 transfusions."
The hepatitis viruses are the primary risk factors for developing liver cancer. Other, nonviral risk factors include the following:- Cirrhosis (a disease that interferes with normal liver function)
- Chronic liver infections
- Exposure to environmental toxins—specifically aflatoxins, a naturally occurring poisonous substance often produced by molds
- Diabetes and some rare metabolic disorders
- Alcoholism, because it can lead to cirrhosis
- Certain genetic mutations
- Older age and male gender
Changing high-risk behaviors, such as needle sharing among drug users and unsafe sexual practices, is the best way to lower the risk of getting a hepatitis infection.
Prevention, Screening, and Treatment
Prevention appears to be straightforward for liver cancer because we know the well-defined risk factors, said Dr. Zhu. "If you block the HBV and HCV infection—called primary prevention—you will reduce the risk of developing liver cancer."
HBV is completely preventable with a vaccine that is commonly available in the United States. However, it is not readily available in other countries, which have much higher rates of HBV. "Increasing availability to this vaccine worldwide represents a very logical step to prevent this particular cancer from developing," said Dr. Zhu. Other prevention methods include educating people about high-risk behaviors that can lead to hepatitis infection.
Currently, no vaccine for HCV is available. "As a result, we still have to continue these very routine but important strategies that include vigorous blood product screening and education about the risks of intravenous drug use and safer sex practices."
Screening those at high risk of developing liver cancer is also an option to prevent or detect the disease early and begin treatment. "It can take as long as 25 years for a hepatitis viral infection to develop into end-stage liver cancer," said Dr. Zhu. "By that time, the prognosis is poor. However, when caught early, it is treatable."
Currently, there are no good ways to screen people at high-risk of developing liver cancer. Research to develop better screening tools is ongoing.
Antiviral medications control the virus for a short time, but eventually stop working. Other medications have some uncomfortable side effects. "We know these drugs are effective in controlling viral infection, but we don't know if these drugs can delay the development of liver cancer," said Dr. Zhu. The only ways to cure liver cancer are surgery to remove the cancerous tissue and liver transplants, he added. Unfortunately, most people with advanced liver disease are not able to have surgery or a liver transplant.
Although liver transplants can successfully treat liver cancer, not enough livers are available. Furthermore, transplantation is not the best way to address a cancer that could be prevented using other measures. As a result, this disease really requires the development of newer drugs. Fortunately, many drugs are being developed, said Dr. Zhu.
Doctors have had some success with chemoembolization and radiofrequency ablation. Chemoembolization involves giving chemotherapy directly into the blood vessels that feed liver tumors. Radiofrequency ablation uses heat to kill cancer cells.
Looking to the future, Dr. Zhu said that the goals of research are to gain a better understanding of the biology of hepatitis infection and liver cancer, specifically how cancer develops in liver cells. In addition, research should focus on the prevention and treatment of hepatitis infections, including the development of new drugs.
The Virus-Cancer link
How a hepatitis virus infection causes cancer is unclear. Although scientists know that the virus causes genetic changes that lead to the uncontrolled growth of liver cells, the specific process remains unknown.
One difficulty is that cancer does not develop immediately after infection with HBV. In some people, the HBV infection is subclinical, meaning they have no symptoms and will probably recover. In other people, HBV leads to sudden, severe liver inflammation or to chronic HBV infection, which means that the virus continues to replicate in the liver.
The way a person responds to an HBV infection probably has to do with when the person gets the infection, said Dr. Zhu. For example, if people develop the infection at birth or in infancy, most will become infected and will carry the virus throughout life. Even so, about 90% of adults who become infected with HBV can get rid of the virus without any further problems. "However, under certain circumstances, this virus can be reactivated, causing chronic hepatitis," said Dr. Zhu. Chronic hepatitis is a major risk factor for liver cancer.
Infection with HCV develops differently than HBV. "We know that upon exposure to this virus, greater than 90% of the people with HCV infection will have a chronic infection," added Dr. Zhu. "Once the chronic infection occurs, an additional 20% will develop cirrhosis. This takes a long time, maybe up to two decades. Once cirrhosis exists, there is a well-defined risk of developing liver cancer, and an additional 25% of this group will actually develop cancer."
Cancer does not develop immediately after contracting HCV. Therefore, if the infection can be blocked or treated effectively, cancer can be prevented, said Dr. Zhu.
Last Updated: September 27, 2004
Helicobacter Pylori and Stomach Cancer
Stomach cancer is the seventh leading cause of cancer death in the United States and the second most common cause of cancer deaths worldwide.
More than 90% of stomach cancers are adenocarcinomas, which means they form in cells that line the inside of the stomach. Other, rare types of cancerous tumors that form in the stomach include lymphomas, gastric sarcomas, and carcinoid tumors.
A bacterium called Helicobacter pylori, or H pylori, has been linked to stomach adenocarcinoma. Bacteria are tiny, living organisms that most people associate with illnesses such as strep throat or ear infections. Although bacterial infections in the human stomach were first described decades ago, it wasn't until the early 1990s that researchers were able to show that H pylori causes stomach cancer.
Incidence and Risk
"H pylori is the most common bacterial infection in the world," explained Charles S. Rabkin, MD, MSc, Senior Investigator of the Viral Epidemiology Branch of the National Cancer Institute (NCI) in Bethesda, Md. People are infected in childhood, generally under the age of three. This tends to be a lifelong infection, unless treated with antibiotics, said Dr. Rabkin.
According to the NCI, H pylori infection is particularly common in parts of Asia and South America, where more than 85% of the population is infected. As a result, stomach cancer is more common in these regions. In developed countries, approximately 40% to 50% of people are infected, but these rates are dropping, primarily because fewer children are developing infections.
Curiously, parts of sub-Saharan Africa with very high rates of H pylori infection have some of the lowest rates of stomach cancer. Moreover, the people there have a very high rate of a precancerous stomach condition, called chronic atrophic gastritis. "People get the infection, and they get some of the early signs of disease that are associated with the infection," explained Dr. Rabkin, "but they do not tend to have a high risk for going on to stomach cancer. That's been called the 'African enigma.'" People have theorized that this enigma may be related to differences in the immune systems of people in sub-Saharan Africa compared to people in the West, possibly caused by differences in certain immune system proteins that may protect sub-Saharans against stomach cancer.
Death from stomach cancers has been decreasing worldwide over the past 50 years, and it has been decreasing equally in high-incidence and low-incidence regions. "The suspicion is that this downward trend is related to the decline in the prevalence of H pylori," said Dr. Rabkin. However, the declines have not been seen in all types of stomach cancer.
Cancers that occur in the cardia (the upper part of the stomach where it attaches to the esophagus) tend to share characteristics with esophageal cancer. Cancers in the noncardia (the rest of the stomach) behave similarly to each other.
"The noncardia cancers are the ones showing the declines," said Dr. Rabkin, "and these make up the bulk of stomach cancer. Unfortunately, cardia cancers are on the rise. Some attribute the rise to the obesity epidemic, which causes esophageal disease and reflux, thereby damaging the esophagus and causing cardia cancer similar to esophageal cancer."
Interestingly, this change in cancer incidence by stomach location may also be linked to H pylori. Evidence suggests that people infected with this bacterium have a lower risk of cardia cancer than people without the infection. The infection—the same one that causes the lower stomach cancers—seems to protect against the development of cancer in the upper stomach.
Studies also show that some types of H pylori are more damaging to human cells than others, and these harmful strains are often present in the upper stomach. However, these so-called "dangerous" strains contain genes that appear to be protective against cancers of the upper stomach. Dr. Rabkin commented that scientists might want to reconsider the goal of eventually eliminating H pylori if it actually contains genes that are protective against cancers of the upper stomach.
Finally, in one type of cancer, infection with H pylori may not start the cancer process, but allows it to continue once a person is already infected. Mucosa-associated lymphoid tissue (MALT) is cancer of the lymph cells that develops in the cells close to the stomach. MALT can also be found in the spleen. In MALT, the cancer cells are not infected, but the presence of the H pylori infection results in the cell's loss of regulatory control.
Curing the bacterial infection can, in some instances, cure this kind of cancer, said Dr. Rabkin. One study showed that 75% of patients experienced a complete cure of their non-Hodgkin lymphoma by specific antibiotic therapy against H pylori. Even though this treatment did not cure all the cases of lymphoma, antibiotic therapy helped such a large number of people that it is now a standard of care, explained Dr. Rabkin.
Risk factors for developing stomach cancer often have to do with differences among people. There appears to be two different patterns of how the human body responds to gastritis (inflammation of the stomach lining). In some individuals, explained Dr. Rabkin, the inflammation is confined to the lower portion of the stomach. In these people, a large amount of acid is generated, resulting in a high risk of a duodenal (the upper part of the small intestine) ulcer.
In contrast, he said, some people develop widespread gastritis, which interferes with the release of stomach acid. This condition leads to gastric ulcer disease. "The risk of developing cancer is increased in people with widespread gastritis. Yet, it's low in people with duodenal ulcer disease. In addition, it's a curious phenomenon that people with duodenal ulcers who, by definition, have H pylori—the risk factor for gastric cancer—have a lower risk of gastric cancer than the general population."
Dr. Rabkin explained that some people have certain genes that make them more likely to have more inflammation when they are exposed to H pylori. This implies that genetics plays a role in whether people infected with H pylori eventually develop ulcer disease or gastric atrophy (a condition where the stomach muscles and digestive glands weaken), which is the first step in the development of stomach cancer.
Other genes may also increase a person's risk. Certain inherited genetic disorders—such as hereditary nonpolyposis colon cancer (HNPCC), also called Lynch syndrome, and another called familial adenomatous polyposis (FAP)—have also been shown to increase the risk of developing stomach cancer.
"While H pylori is a leading cause of stomach cancer, there are a host of other factors not related to the bacterium or to genetics," said Dr. Rabkin. "Some of these include diets high in salt, previous stomach surgeries or stomach disorders, exposure to certain dusts or fumes, and excessive tobacco or alcohol consumption. Eating fresh fruits and vegetables may help lower risk."
Prevention, Screening, and Treatment
Advances in treating stomach cancers will continue to reduce the death rate from this disease. Surgery, chemotherapy, and radiation are standard options for treating stomach cancers. Antibiotics are the first line of defense against H pylori infection to treat ulcer disease and possibly prevent cancer from developing or, in some cases, treat the cancer itself. "Although not yet proven, there's the chance that H pylori may be protective against other types of stomach cancer. Therefore, we should move ahead with caution as we look at the potential effects of eradicating the bacterium," Dr. Rabkin stated.
The Virus-Cancer Link
How an infection with H pylori causes cancer is still being studied. Doctors know that H pylori can survive in the low-oxygen conditions of the stomach by producing an enzyme that helps neutralize stomach acid and kills most other harmful bacteria. In addition, H pylori secretes a toxin, which is a lipopolysaccharide (LPS) that overloads the immune system and allows the bacteria to survive.
In response to the infection, the body produces white blood cells, which trigger inflammation. The resulting gastritis is the first step in the H pylori-related disease process. Gastritis can then lead to metaplasia—the replacement of cells of one type by another type. Eventually, metaplasia leads to the final stages of malignant transformation dysplasia (abnormal cell growth), and finally, cancer.
"It's a universal phenomenon that people with H pylori infection develop gastritis," said Dr. Rabkin. "It's always present; everybody gets it, yet most people don't have symptoms. Remarkably, the diseases that are associated with this infection occur in just a small fraction of people."
For example, ulcers occur in approximately one in 10 individuals that have H pylori infection. Two types of stomach cancers—gastric lymphoma (cancer of the lymph cells) and gastric adenocarcinoma (cancer of the stomach lining)—occur in just 1% to 2% of people who have the infection for many decades. "It's a question as to why certain individuals develop these consequences, yet most people live perfectly normal lives unaffected by the infection," commented Dr. Rabkin.
Last Updated: September 27, 2004
Human Immunodeficiency Virus (HIV), Human Herpesvirus-8 (HHV-8), and Kaposi's Sarcoma (KS)
HIV, the virus that causes acquired immune deficiency syndrome (AIDS), attacks the immune system and leaves the body vulnerable to a variety of life-threatening illnesses and cancers. One of these diseases is Kaposi's sarcoma (KS), a rare cancer that causes red and purple blotches (lesions) that appear just below the surface of the skin.
The skin blotches that are associated with KS are a mixture of cancerous, precancerous, and inflammatory cells. These cells cause the body to create a network of blood vessels and connective tissues below the surface of the skin to support the tumors. These cancerous lesions, although disfiguring, are not usually life threatening. However, they can spread to the lymph nodes, lungs, liver, or the digestive tract and, if so, can be fatal if left untreated.
Until the onset of the HIV/AIDS epidemic in the United States, KS occurred primarily in older men of Mediterranean or Jewish descent, children and young adults in Africa, and organ transplant recipients.
There are four types of KS:- Classical, which occurs most often in elderly men of southern European and Middle Eastern origin, and is usually confined to the arms and legs.
- Endemic, which has existed for many decades in both adults and children in some African countries. It is more high-risk than classical KS.
- Post-transplant, which can occur in organ transplant recipients because of immunosuppressive drugs that are used to prevent organ rejection. Transplant recipients are 150 to 200 times more likely to develop KS than the general population.
- AIDS-related, which is the most common form of KS in the United States today. Because of the successful treatment of AIDS with newer drugs, this form of the cancer is less common in developed countries, but it is the most common type of cancer in several African countries.
Incidence and Risk
In the United States, approximately 1.5 million people have KS. It is two to three times more common in men than in women. "Kaposi's sarcoma is now the leading cause of cancer in men and women in several areas of sub-Saharan Africa, and it is the number one cause of cancer in South Africa and Uganda," said James J. Goedert, MD, Chief of the Viral Epidemiology Branch at the National Cancer Institute in Bethesda, Md.
People with advanced HIV infection are 100,000 times more likely to develop KS as compared with people without HIV infection, said Dr. Goedert. A study of an African population identified other risk factors for KS, including a history of asthma, use of topical corticosteroids (medications that are applied to the skin to treat inflammation), bathing less than once a week, and perhaps most strikingly, not smoking.
"In this study, people who smoked were about four times less likely to develop the disease than those who did not smoke," said Dr. Goedert, adding that this phenomenon is currently under study. After the outbreak of AIDS, there were numerous clues that a second virus other than HIV was linked to KS. In 1994, researchers identified a virus called human herpesvirus-8 (HHV-8) or Kaposi's sarcoma herpesvirus (KSHV), as the second virus.
HHV-8 is distantly related to Epstein-Barr virus (EBV). HHV-8 is transmitted sexually, although studies have shown that HHV-8 can be transmitted through saliva, which is how children in Africa and the Mediterranean region most likely contract the virus.
Approximately 5% of people in the United States are infected with HHV-8. In parts of Africa, 50% of the population, or 27 million people, are infected with HHV-8. The virus is a growing problem in eastern Europe and southern and eastern Asia as well.
Various factors increase a person's risk of infection with HHV-8.- Some studies indicate that intravenous drug use and infection with the hepatitis C virus can increase a person's risk of HHV-8 infection by as much as three-and-a-half times.
- More than one-third of those who have AIDS and antibodies against HHV-8 (indicating that the virus has been present in the body) are estimated to develop KS within 10 years.
- Among those who have both HHV-8 antibodies and HHV-8 DNA in their blood, 30% are estimated to develop KS each year.
"The risk of getting the disease if you have AIDS and you have the virus in the blood is extraordinarily high," emphasized Dr. Goedert. He believes that controlling the HHV-8 infection or preventing the infection altogether would have a significant impact on controlling the spread of KS.
Prevention, Screening, and Treatment
The treatment of KS may include chemotherapy, radiation therapy, surgery to remove the lesions, interferon treatment (which stimulates the body's immune system), and antiviral therapies. These include ganciclovir (Cytovene), cidofovir (Vistide), and foscarnet (Foscavir). Of these, ganciclovir seems to be the most effective in controlling the virus.
Another strategy is to prevent or treat the underlying HIV or HHV-8 infection. For example, when highly active anti-retroviral therapy (HAART) was introduced for people with AIDS, there was a sudden reduction in the risk of KS among people with AIDS. "It's truly stunning and profound in terms of the impact that HAART has had on the cancer that's caused by the KS herpesvirus, said Dr. Goedert." In addition, the development of a vaccine or drugs that target HIV and HHV-8 may also help prevent KS.
Because of their weakened immune systems, people with HIV/AIDS are also at a much greater risk of developing other types of cancers. For example, there is a 230-fold increase in developing non-Hodgkin lymphoma. These people are also at a greater risk of developing anal and cervical cancers and Hodgkin lymphoma.
Despite advances in treatment for AIDS patients, the disease remains a major health burden in the United States. "The population of people living with HIV and AIDS is growing in this country and new infections continue to develop. These patients are better off than they were before because of antiretroviral therapy, but we have more HIV/AIDS patients than ever before. But beyond the United States, specifically in Africa, the HIV/AIDS epidemic is stunning in its magnitude. There is much more work to be done," said Dr. Goedert.
Last Updated: September 27, 2004
Glossary of Terms
Acute infection: An infection that begins quickly and lasts for a short time
Antiviral therapy: Any drug that inactivates or kills a virus
Antiretroviral therapy: A specific type of drug that acts against a group of viruses called retroviruses (such as the human immunodeficiency virus [HIV])
B cell: A type of white blood cell in the immune system that helps fight infection by making antibodies
Bacteria: Single-celled living organisms, some of which cause disease and infection
Clinical trial: Research studies that test new treatment and prevention methods to find out if they are safe, effective, and better than the current standard of care (the best known treatment)
Chronic infection: An infection that develops slowly over many years, with or without symptoms
Lesion: An area of irregular tissue
Lymphocytes: A type of white blood cell that is involved in the immune response to viruses and tumors.
Lymph nodes: Small organs that are clustered in the neck, the armpits, the groin, and along the abdomen that filter lymph (clear, colorless fluid of the lymph system that helps fight infection) and add lymphocytes to the immune system
Immune system: The group of organs and cells that help protect the body against disease and infection
Incidence: An estimate of the number of new cases of cancer diagnosed in a given population (such as all men in the United States) over a specific time—usually one year
Infection: The invasion and multiplication of bacteria, viruses, or fungi in the body
Retrovirus: A virus that uses RNA as the genetic material, such as the human immunodeficiency virus (HIV). Retroviruses have a unique way of incorporating their genes into the infected cell.
Risk: The probability that an event will occur, such as the probability that a person will develop cancer
Risk factor: Anything that increases a person's chance of developing a disease such as cancer
T cell: A type of white blood cell in the immune system that kills cells infected with bacteria and viruses
Transmission: The process of spreading a viral infection from one person to another
Viral: Having to do with viruses
Virus: A tiny, nonliving entity that can cause infection and disease
Last Updated: September 27, 2004
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