July 22, 2005

By Lynette Grouse and Mike Miller

Posted in: lymphoma

Tags: ALL, blood, CLL, CML, EBV, Hodgkin, leukemia, lymphoma, myeloma, non-Hodgkin

Lymphoma is the fifth most common cancer in the United States and represents over forty subtypes of cancers arising within the lymphatic system. The two most prevalent types are Hodgkin’s and non-Hodgkin’s lymphomas. Of the 63,700 estimated new cases of lymphoma in 2005, non-Hodgkin’s lymphoma accounts for about 88 percent of those cases. The incidence of non-Hodgkin’s has increased, nearly doubling over the past 30 years. Researchers speculate that the increase may be due in part to environmental agents triggering genetic factors which initiate malignancies. Hodgkin’s lymphoma, with 7,000 new cases predicted in 2005, is a less prevalent disease. The cause of most lymphomas is unknown, but a compromised immune system and exposure to carcinogens, bacteria and viruses may play a role. The incidence of lymphoma is increased in patients infected with Epstein-Barr virus (which causes mononucleosis) or HIV.

Lymphomas result when cells in the immune system multiply uncontrollably. The immune system is maintained by lymphocytes; T-cells and B-cells, each playing specific roles in fighting disease. The T-cells are lymphocytes that attack bacteria and viruses invading the body, while the B-cells, as mature plasma cells, produce antibodies to ward off infections. All lymphocytes develop in the lymphatic system, a network of thin tubes that branch and widen to form lymph nodes. Clusters of lymph nodes are found under the arms, and in the groin, neck, chest, and abdomen. Other lymphatic tissues include the spleen, thymus, tonsils, and bone marrow. The lymphatic vessels contain colorless, watery fluid called lymph in which the lymphocytes constantly circulate between peripheral blood and lymph nodes.

Non-Hodgkin’s lymphoma can result from the overproduction of T-cells or B-cells and is not a single disease, but rather a group of closely related cancers that affect the lymphatic system. This type of lymphoma tends to disseminate to various parts of the body through the lymphatic system.Non-Hodgkin’s lymphoma can be divided into two groups based on prognostic factors of tumor growth; indolent and aggressive. The indolent forms have a good prognosis and can be effectively treated with radiation therapy. However they are rarely cured in advanced stages. The aggressive forms of non-Hodgkin’s lymphoma have a poor prognosis, but a significant number of patients can be treated effectively with intensive chemotherapy. The overall five-year survival for all non-Hodgkin’s lymphomas is 50 percent to 60 percent. However, a great number of patients relapse within two years following therapy.

Hodgkin’s disease is a less commonly diagnosed lymphoma that occurs mainly in young adults between the ages of 16 and 32 and older patients over the age of 55. The overall five-year survival rate is about 85 percent. A diagnosis of Hodgkin’s lymphoma is dependent upon the observation of abnormal cells, called Reed-Sternberg cells, a hallmark of this disease. Unlike non- Hodgkin’s lymphoma that spreads throughout the body, Hodgkin’s lymphoma tends to spread to adjacent lymph nodes in sequence before invading other organ sites. Today, Hodgkin’s lymphoma has a high survival rate due to improved diagnosis and treatment regimens. Many patients receive radiation, chemotherapy or a combination of both and are able to lead healthy lives.

To discuss various current aspects of lymphoma treatment and diagnosis, NCI staff sat down for an interview with Wyndham Wilson, M.D., Ph.D., NCI, head of the Lymphoma Clinical Research Section (LCRS). The LCRS serves as an advisory group to basic and clinical scientists interested in testing new agents and treatment strategies for malignant lymphoma.

Q: Leukemia, a disease of the blood, is carried by a very large vascular system. The lymphatic system isn’t quite as extensive and yet we are having more difficulty treating lymphoma than leukemia? Why is this the case and is there a basic biological understanding we’ve gained in comparing the two types of diseases?

A: I’m not sure we are having more trouble with lymphoma than leukemia. First off, lymphomas are much more common. Secondly, they are comprised of over 30 subtypes with more being added as we understand their biology. Because there is such diversity, it is impossible to clinically lump them together. For the most common type, called diffuse large B-cell lymphoma, we have made important advances in curing the disease. For other types, such as follicular lymphoma, the second most common type, we have made advances in treatment using targeted treatments and monoclonal antibodies.

Q: Do we know why that would be? Why would you have more cancers of the lymphatic system than of the vascular system?

A: Probably because lymphomas are a disease of lymphocytes. When a cell divides, it is at higher risk of obtaining chromosomal abnormalities. Normal immune function involves a selection process that leads to the division of millions of lymphocytes. Furthermore, these cells rearrange their genes as part of the selection process. Thus, the sheer number of lymphocyte divisions and their intrinsic biology puts them at higher risk. For example, there is an increased risk of lymphoma in patients with autoimmune disorders where there is an abnormal activation of the immune system.

Q: Such as rheumatoid arthritis?

A: Yes, rheumatoid arthritis is associated with an increased incidence of lymphoma. Probably the more activation there is, the higher the risk that the right combination of molecular events which could lead to lymphoma will occur. Chronic lymphocyte activation can also occur with infectious diseases. Viruses, such as Epstein-Barr, can stimulate lymphocytes to divide and is associated with several lymphoma subtypes, such as Burkitt’s lymphoma. Emerging evidence also suggests there may be a genetic predisposition to lymphoma as well.

Q: Are there any distinguishing characteristics between adult and pediatric lymphomas?

A: There are differences in the relative proportion of lymphoma subtypes in children vs. adults,but all types occur in both groups. Within similar subtypes, there have not been adequate scientific studies of biological differences. However, pediatric patients generally have a better clinical outcome than adults with the same subtype. In part, this may due to differences in treatment and tolerance. However, there are likely to be biological differences as well which involve the pathways in the development of lymphoma.

Q: In the 1970s, for Burkitt’s lymphoma, researchers were looking at Epstein-Barr virus (EBV) titers or levels to try to understand the disease. How has the understanding of lymphomas changed from looking at elevated titers in the 1970s to using microarrays in the 21 st century?

A: The earlier studies linked EBV to Burkitt’s but did not address pathways of transformation. However, today, we are gaining a better understanding of the mechanisms of transformation that lead to lymphoma. Microarrays are a tool to look at the genetic expression fingerprint of tumors which can help elucidate pathways. Other viruses have also been associated with lymphoma.

Q: So are there other viruses that play roles similar to EBV?

A: Yes. HTLV-1 is associated with adult T-cell lymphoma and HIV is indirectly associated with B-cell lymphoma. Mechanistically, these viruses will have different ways of leading to lymphoma. Among all of these, however, EBV appears to be the most common virally associated cause of lymphoma. People don’t realize that about 90 percent of us have been exposed to EBV and most of us never know why.

Q: After a bout of mononucleosis?

A: Most people who get EBV never know it. Mono is when you become symptomatic. O ur bodies never eliminate EBV totally and it lies dormant in a small number of our B-lymphocytes for the remainder of our lives.

Some patients who become immunocompromised lose the ability to regulate EBV and the EBV can stimulate the B-cell to divide. This process may lead to a lymphoproliferative disorder and ultimately to lymphoma if the process is not controlled. That’s why aggressive lymphomas in immunocompromised settings are often EBV positive.

Q: So do we know, comparing all lymphomas, what make some more aggressive than others? Is it a turning on and off of, say for example, the myc gene?

A: Overexpression of the myc gene is associated with more aggressive clinical behavior. However, this is just one of many events that can lead to aggressive lymphomas. .

Q: Is it a host of factors? Could it be due to just one DNA translocation?

A: Yes, it’s a host of factors and depends on what gets turned on. Take, for example, indolent lymphomas — indolent because their general natural history is one of a slow going pace. Some lymphomas are relatively rapidly growing and others are not. Researchers identified cases where there’s amplification of myc in some of these low grade diseases; in these cases, the disease acts in
an extremely aggressive fashion.

Q: So is there any equivalent to a leukemia such as chronic lymphocytic leukemia (CLL), which for ten years can be indolent and then move to a devastating blast phase?

A: Yes. But it’s a little bit different. The equivalent for indolent lymphomas is histological transformation to a more aggressive disease. This reflects clonal evolution, where a clone gets additional hits. Once these things become tumors or become lymphomas, they become independent of normal regulatory pathways. They have a higher tendency to accumulate and to survive additional hits.

When you have an indolent process for years, over time it’s just natural that you’re going to get clonal evolution.

In chronic lymphocytic leukemia, we call it a Richter transformation. One of the major ones in Richter’s transformation is a mutation of the p53 gene, which is a gene that actually is involved to some extent in surveying damage, arresting the cells, and turning on apoptotic pathways.

Q: For lymphomas, have we accumulated a base of knowledge in terms of the history of treatment, from doing something that’s very systemic to one that’s targeted, a la the Gleevec model for CML?

A: You first have to understand where the actual targets are. A genetic hallmark of CML is the translocation of the C-abl gene which can be targeted for treatment. Gleevec is a small molecule inhibitor that interferes with the function of this gene.

In contrast, a specific genetic target has not been identified for most lymphomas. In large cell lymphoma, for example, there are many genetic abnormalities that have been identified, but not a single one that can be targeted thus far. With microarrays, however, we are identifying potential new targets and studies are underway to test new agents.

Q: In terms of clinical trials, is there anything that you’d want to say in terms of patient populations or how clinical trial recruitment is going for some of the studies you’re doing?

A: I think that we must increase accrual to clinical trails in the United States. Compared to European studies, for example, the United States has done an inadequate job of accruing to clinical trials. The problems are due to our medical system of private practice and to our clinical trial system. One important area is patient education on studies and access to clinical trial lists.

Q: ClinicalTrials.gov or NCI’s clinical trials Web site at http://www.nci.nih.gov/clinicaltrials would be great places to start!

Animation/Video

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Text Transcript

B Cells and T Cells: An Animated Tutorial

Cancer vaccines, whether to prevent or treat cancers, take advantage of the immune system’s ready-made network of cells and organs that work together to defend the body against attack by “foreign” invaders. When a foreign organism or entity (an antigen) enters the body, a variety of immune cells and molecules mount an appropriate response. Lymphocytes are one of the main types of immune cells. The most common lymphocytes, B cells and T cells, patrol the blood and lymph system for foreign antigens. Cancer vaccines currently under development are designed to stimulate primarily B or T cells to mount an attack against foreign entities.

The job of the B cell is to ambush antigens circulating in the bloodstream. Protruding from its surface are antibody molecules poised to bind foreign agents such as toxins, bacteria or viruses. Only specific antigens will bind to each B cell.

Once the triggering antigen binds, the B cell digests it, and displays antigen fragments with the help of a marker molecule on the cell surface.

The antigen/marker combination is recognized by a T cell, which in response secretes lymphokines.

These, in turn, stimulate the multiplication and maturation of B cells into plasma cells. The plasma cells pour millions of identical antibody molecules into the bloodstream.

These antibody molecules ambush and inactivate the matching antigens in the blood.

While B cells attack soluble antigens in the body’s fluids, the job of the T cells is to attack cells that have either been infected by viruses or altered by cancer.

Cells that display pieces of foreign antigens on their surface with the MHC molecule are called antigen presenting cells (APC). APCs are either B cells, macrophages or dendritic cells. T cells recognize antigens only when they are bound to cell-membrane proteins called major histo-compatibility complex (MHC) molecules. Cells that display pieces of foreign antigens on their surface with the MPH molecule are called antigen presenting cells (APC). APCs are either B cells, macrophages or dendritic cells. T cells recognize antigens only when they are bound to cell-membrane proteins called major histo-compatibility complex (MHC) molecules.

When a T cell is activated by binding to the antigen/MHC complex, it secretes lymphokines. The secreted lymphokines cause several reactions.

Some Lymphokines spur the growth of Memory T cells. Memory T cells are primed to fend off additional attacks by the same antigen. These have a longer lifespan in the body and respond more readily to a second antigen assault than the original T cell. Some T cells become natural killer T cells, known as cytotoxic T cells (or CTL), which attack infected or abnormal cells directly.

Some T cells become natural killer T cells, known as cytotoxic T cells (or CTL), and attack infected or abnormal cells directly. The lymphokines also attract other immune cells, such as macrophages and neutrophils, to the site of the foreign invasion.

Audio Clips

1. Dr. Wyndham Wilson, NCI, discusses lymphomas vs. leukemias.

      ( Audio – Length: 1:06 – 784 kb )

   Text Transcript

   Dr. Wyndham Wilson, NCI, discusses lymphomas vs. leukemias.

   Q: Why are there more cancers of the lymphatic system than of the vascular system?

   A: Probably because lymphomas are a disease of lymphocytes. Anytime a cell starts to divide, it’s at higher risk of getting additional hits. In contrast with a myeloid cell, the myeloid cell is there. But you have a system like the lymphoid system where our lymphoid cells are. What they do for a living is they just divide and stimulate constantly, constantly, constantly. And I think the sheer number of all these different things going on just puts them at higher risk.

   In fact, we know from a conceptual point of view that that is in fact a risk. Because if you look at autoimmune disorders, where there is an abnormal activation of the immune system, it’s usually lymphocytes against a normal target. Those patients all have an increased risk of getting lymphoid diseases.

2. Dr. Wyndham Wilson, NCI, discusses indolent lymphomas.

      ( Audio – Length: 2:21 – 1.66 MB )

   Text Transcript

   Dr. Wyndham Wilson, NCI, discusses indolent lymphomas.

   Q: Is there any equivalent to a leukemia such as chronic lymphocytic leukemia (CLL), which for ten years can be sort of indolent and then move to a devastating blast phase?

   A: Yes. But it’s a little bit different. The equivalent for indolent lymphomas is that most of them have a tendency, some more than others, to undergo histological transformation to a more aggressive disease. So that reflects clonal evolution, where a clone that gets additional hits. Once these things become tumors or become lymphomas, they become independent of normal regulatory pathways. They have a higher tendency to accumulate and to survive additional hits. And so what happens over time is that when our normal cells get genetic hits, our cells have huge amounts of surveillance pathways to kill those cells. Those cells die. Otherwise, we would be popping up with tumors all the time. Because our genetic code probably gets hit constantly. You know, our body fixes them or the cells commit suicide through the apoptotic pathway. Tumor cells have a much higher tendency of, number one, not transcribing their code correctly. And number two, not committing suicide when the hit happened. So when you have an indolent process, a chronic process, that you have for years and years and years, over time it’s just natural that you’re going to get clonal evolution. A clone that gets a hit that gives it a proliferative advantage. And something’s going to pop up. And that’s what happens in CLL when it undergoes a blastic transformation. In any of the lymphomas, they undergo a large cell transformation.
   

Photos/Stills

1. Lymphatic system (neck to upper thigh shown), part of the body’s immune system. Clusters of lymph nodes are found in the underarm, groin, neck, and abdomen.

2. Lymphoma tumor cells.

3. Acute myelocytic leukemia (AML).