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Lymphomas are a group of diseases and we divide them into Hodgkin’s disease and non-Hodgkin’s lymphomas. It’s always interesting that we’ve named the non-Hodgkin’s lymphomas non-Hodgkin’s lymphomas even though those are the more common kinds of lymphomas. These are cancers caused by growth of malignant lymphocytes predominantly in lymph nodes but certainly this can be seen in other tissues. Most of the time these are B-lymphocytes about 85% of the time but sometimes these are T_lymphocytes lymphoma, limphoma, limfoma, non-hodgkins lymphoma, nonhodgkins lymphoma, hodgkins lymphoma, hogkins lymphoma, hodgkin lymphoma
Just to put things in perspective, I just want to point out that these are not the most common diseases that we see. Lymphomas only represent about 3 or 4% of all new cancers in
Just to put things into perspective, there’s 180,000 new cases of prostate cancer, 170,000 new cases of lung cancer, 180,000 cases of breast cancer, 130,000 new cases of colorectal cancer. So these are not the most common cancers but I think the reason I think it’s so important to talk about lymphomas is because much of what we know about treatment for any kinds of cancers comes from what we know from lymphoma. By that, I mean these were among the first kinds of
We don’t really even know what the etiology of the Reed-Sternberg cell is – the pathologic cell in Hodgkin’s disease. It used to be thought that this was a monocyte or macrophage. Now there’s very good evidence, in fact, I think definitive evidence that this is a lymphocyte. But in some cases it appears to be a T-lymphocyte and in other cases this appears to be a B-lymphocyte. There is some evidence that this is a T-cell because of certain lymphocyte markers and because some of the time these patients have T-cell receptor gene rearrangements. On the other hand, sometimes the patients have B-cell markers. Sometimes they have immunoglobulin gene rearrangements indicative of a B-cell etiology and sometimes they have chromosomal abnormalities like we see with B-cell lymphomas. So it’s not really certain what this cell is but I think it’s safe to say that this is a lymphocyte but sometimes it appears to be a T-cell and sometimes a
Let me talk a bit about non-Hodgkin’s lymphoma. Just briefly, on the left panel is a patient with a diffuse lymphoma and on the right panel is an example of someone with a nodular lymphoma. This is referred to actually as a follicular lymphoma. So the terms nodular and follicular are interchangeable. The point I want to make is that you’ll hear and see these terms
I think one of the most important things with respect to non-Hodgkin’s lymphoma is the fact that there’s an epidemic of non-Hodgkin’s lymphoma. If you look at this curve, this shows the U.S. incidence rate and mortality for white males and you can see that the incidence rate is increasing about 3 or 4% per year. The mortality rate isn’t increasing quite so rapidly
The other thing that’s interesting with respect to these lymphomas that are seen in people with AIDS or people who have had solid organ transplants are the fact that they are very aggressive lymphomas. The life expectancy or the median survival for people with AIDS and non-Hodgkin’s lymphomas is about six months. These lymphomas tend to be very
We also know that there is a fair amount of evidence linking viruses to non-Hodgkin’s lymphoma. The best example is Epstein-Barr virus. Now I think you know the story linking Helicobacter to certain kinds of lymphoma and you all know the story about Helicobacter and gastric ulcers. Now there is a kind of lymphoma called MALT lymphomas or gastric MALT lymphomas and MALT stands for mucosa associated lymphoid tissue. These are generally low grade gastric ulcers and now there is really quite a bit of evidence, both epidemiologically and experimentally, linking the association of Helicobacter to these low grade gastric MALT lymphomas. I’ll talk about at the end of the talk the fact that now sometimes these can be treated with antibiotic therapy in exactly the same manner as we treat ulcers.
Finally, there’s a number of environmental etiologies that have been identified for non-Hodgkin’s lymphoma and I bring this up because there’s a fair amount of evidence linking herbicide exposure to the development of non-Hodgkin’s lymphoma. I think your patients may ask you about this. There are any number of epidemiologic studies including a very good one done here linking exposure with the herbicide 2-4-D with non-Hodgkin’s lymphoma. Not everybody believes these studies and, in fact, since these studies were done, the manner of application and safety in administering these herbicides has been increased and so maybe this doesn’t apply like it did in the 1970s or 1960s when the data was
Your patients may also ask you about hair dye. In fact, there was a large study done in linking hair dye and non-Hodgkin’s lymphoma. In fact, it was said that as many as 50% of the lymphomas in women could be related to the use of hair dye. For whatever it’s worth, there’s been a subsequent study in nurses that found no relationship between the use of hair dye and non-Hodgkin’s lymphoma if patients ask you about this.
The other thing I just want to touch on briefly is cytogenic abnormalities in non-Hodgkin’s lymphoma. This is a major area of interest and the only point I want to make is that most lymphomas are associated with chromosomal abnormalities and that certain chromosomal abnormalities are associated with certain kinds of lymphomas. The other point is that each of these chromosomal abnormalities occurs at the site of known oncogenes. These chromosomal translocations result in overexpression of these genes that are somehow related to the development of the non-Hodgkin’s lymphoma.
Just as one example, ECL-2 is a gene that inhibits programmed cell death so it’s not hard to believe that if you have more of this gene that inhibits the death of lymphoma cells, then in some way this is linked to the development of the lymphoma. We’re finding this out more and more for each kind of lymphoma that each kind of lymphoma is associated with certain specific chromosomal abnormalities that are in some way related to the development of these lymphomas.
Hodgkin’s disease. We use the Rye classification. Having shown you this, it’s not quite certain that patients with lymphocyte predominant histology have an outcome different than lymphocyte depleted histology stage for stage. Now, in general, lymphocyte depletion histology occurs in elderly patients but these are also patients that are more likely to have advanced disease at the time of diagnosis. Almost all Hodgkin’s disease is nodular sclerosis. That’s the most common kind that you’ll see.
Briefly, some words about classification on non-Hodgkin’s lymphoma because there’s a new classification system you’ll be hearing about. In the past we’ve used the working formulation. I think the thing that’s important for you to know is that there are low grade lymphomas. These are indolent lymphomas. These are generally lymphomas that are incurable. On the other hand, people frequently live eight or ten years even without therapy. Intermediate grade lymphomas are the most common garden variety of lymphomas. These are the lymphomas that are curable about half of the time with chemotherapy. High grade lymphomas are relatively rare in adults but these are the lymphomas that are very aggressive and frequently treated more like leukemia than lymphoma.
I think you’re going to be hearing about something called the REAL, Revised European American Lymphoma, classification. This classification is in your handout. The only point I want to make is that this has a number of advantages over the working formulation but perhaps the chief advantage is that this includes some entities called mantle cell lymphoma and marginal zone lymphomas, some entities that weren’t included in the working formulation. So I don’t want to spend much time on this. I just wanted to make the point that I think you’ll be hearing about this and this includes some entities that were not included in the working formulation.
Now, as you know, the most common presentation of lymphomas is adenopathy but sometimes these people have enlarged livers or spleens. They may have abdominal pain or a mass. They may have GI bleeding from gastric lymphomas. They may have B symptoms – fevers, chills or night sweats or sometimes they come to us because of laboratory abnormalities.
We use the Ann Arbor staging system. This is also in your handout. Stage I is localized disease. Stage II is two sites on the same side of the diaphragm. Stage III is disease on both sides of the diaphragm and Stage IV is diffuse extranodal involvement such as bone marrow, liver, central nervous system.
The reason staging is important is because this influences prognosis and this influences treatment. The other reason staging is important is because if we know all the places patients have disease prior to treatment, then we go back and restage them after treatment to find out if we’ve eradicated the disease.
We also talked about symptom status. Symptom Status A is without symptoms. B symptoms refer to fevers, weight loss and night sweats. This is important because particularly in Hodgkin’s disease, people who have these symptoms have a worse prognosis and may be treated differently than people without these symptoms and that’s the reason we question people about this.
Everyone gets a history and physical examination, lab, CT and bone marrow. Some patients may get additional studies such as a gallium scan which sometimes can help to distinguish between residual fibrosis in lymph nodes from active lymphoma. Sometimes we use a lymphangiogram although not very much anymore and sometimes we use a staging laparotomy in Hodgkin’s disease although not very much anymore.
For limited stage Hodgkin’s disease, which is generally Stage I and II, we have traditionally used radiation although there are now a lot of concerns about using a staging laparotomy before radiation and because of second malignancies from radiation. We’re now learning that particularly in women who have received chest irradiation, there’s an incredibly high incidence of breast cancer and that's why people are getting more and more concerned about using radiation and so there’s been a switch from radiation for limited disease to the use of chemotherapy.
So some people are still recommending radiation. Some people have shifted all the way over to using chemotherapy for limited stage disease. Other people are using a limited amount of chemotherapy and a limited amount of radiation. There is now no consensus on the best way to treat limited stage Hodgkin’s disease although I think most people are now looking at using a limited amount of chemotherapy, a brief course of chemotherapy and then smaller fields or lower doses of radiation.
Advanced stage disease is always treated with chemotherapy with or without radiation. There are any number of treatment regimens that have been used. MOP was the one you’re probably most familiar with. This is the one that’s traditionally used although more and more people are using these other regimens that are in your handout: ABVD, MOP ABVD, MOP ABV. The advantages of these are they are felt to have a lower incidence of fertility problems and a lower incidence of secondary leukemias. At the University of Nebraska, we’re now using a regimen called Stanford 5 in which the chemotherapy is all administered weekly and it’s finished in twelve weeks rather than over
Non-Hodgkin’s lymphoma. For treatment of low grade lymphoma, patients with localized disease will generally get radiation, perhaps with a short course of chemotherapy. There is no consensus on treatment of patients with disseminated disease. Some people recommend observation. These people have low grade, indolent, slow growing asymptomatic disease and sometimes we recommend a watch and wait approach. Other patients will receive single agent or combination therapy.
For advanced disease, Stage II, III or IV, non-Hodgkin’s lymphoma, there are any number of chemotherapy regimens that have been recommended. This is just a short list of the regimens that have been recommended. I want to make a point that in 1993 there was a large study and basically the point is that all the regimens are equal in efficacy and that’s why probably the one regimen you should know or have heard of is CHOP.
So, for patients with intermediate grade disease, if it’s Stage I, they get a short course of chemotherapy and radiation. Disseminated disease is one of these combination chemotherapy regimens.
It is important to give the chemotherapy on time, at full doses in the way that recipe specifies. A study showed that basically patients who received full dose therapy had a 65% complete remission rate as compared with 29% for patients who received less than full dose therapy. The relapse free survival at three years was lower in patients with reduced doses of therapy and the overall survival was about half for patients who received reduced doses of