Dr. Francine Foss, What to Expect when Diagnosed with
Lymphoma
June 6, 2010
Welcome to Yale Cancer Center Answers with Dr. Ed Chu and Dr. Francine Foss, I am Bruce Barber. Dr. Chu is Deputy Director and Chief of Medical Oncology at Yale Cancer Center and Dr. Foss is a Professor of Medical Oncology and Dermatology specializing in the treatment of lymphomas. If you would like to join the conversation, you can contact the doctors directly. The address is canceranswers@yale.edu and the phone number is 1888-234-4YCC. This evening Ed welcomes his co-host Dr. Francine Foss. Dr. Foss is a Professor of Medical Oncology and Dermatology at Yale Cancer Center and this evening she'll be discussing her specialty, lymphoma. Here is Ed Chu.
Chu
Francine let's start off by having you describe for listeners out
there, what made you decide to specialize in hematologic
malignancies, which are also known as liquid tumors?
Foss
It really dates back to my interest in looking at blood under the
microscope, which started at a very early age, but then when I went
to the National Cancer Institute I was very impressed by Dr.
Vincent DeVita, who formally was the Cancer Center Director here at
Yale Cancer Center. Vince was the Director at the National Cancer
Institute and a world leader in developing therapies for
lymphoma. We had a very strong program in lymphoma at the NCI
and I got interested in doing some basic research in lymphoma and
from that I went on to develop a specific interest in the T cell
lymphomas.
Chu
I think many of our listeners may know that Dr. Foss and I actually
trained together at the National Cancer Institute in the 1980s and
as you say Francine, the National Cancer Institute at that time was
the Mecca for lymphoma research, and so I can see how that
generated a great deal of enthusiasm on your part.
Foss
Exactly, and it was a tremendous pleasure to be able to work with
somebody like Dr. DeVita.
Chu
It was amazing, obviously Dr. DeVita as Director of the NCI and
leading the lymphoma research effort, but it was really a whose who
of the lymphoma experts in medical oncology, radiation oncology,
who were there in Bethesda at that time.
Foss
Exactly, and another area that was specifically strong was the
pathology and in fact, Dr. Allan Jaffe has been one of the key
people in developing the new lymphoma classification system, and I
think that's one way that lymphoma has really changed over the last
15 or 20 years. We started out with a very basic
classification system of low, intermediate, high grade, B cell
lymphomas, and T cell lymphomas and now we have got the WHO
classification system that has broken these diseases down into very
specific
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entities based on new information about the molecular
characteristics of these different tumors.
Chu
It seems to me what has really evolved to the greatest extent is
our molecular understanding of the molecular genetics and the
biology of these various lymphomas.
Foss
Exactly, as we have done more and more genetic testing and learned
more about the biology of these different subtypes of lymphoma, we
now have many, many different categories and many specific names
for these different subtypes.
Chu
Obviously it's a very complicated field, but for our listeners can
you break it down very simply as to the different types of
lymphomas that you deal with?
Foss
Basically you can think about lymphoma in broad categories, first
of all Hodgkin's and non Hodgkin', then when you go beyond that and
look at the non Hodgkin's lymphomas, which are by far the more
common types, they basically breakdown into the B cell and T cell
types and within each of those categories there are lymphomas that
are low grade or have a low grade behavior in the patient, an
intermediate grade, and then the high grade lymphomas and then
within each of those categories there are number of different
subtypes as well.
Chu
How common is lymphoma as a disease?
Foss
It's surprising, and most people don't think about this, but
lymphoma is the fifth most common malignancy in the United
States. Within the state of Connecticut, there is an average
of a thousand cases per year and that number is increasing not only
here in Connecticut, but overall in the country as well.
Chu
Why is the incidence of lymphoma increasing here in the state of
Connecticut?
Foss
The incidence is increasing overall for a couple of different
reasons, one of which is that we are living to be older, and if you
look at both lymphoma and other hemological malignancies like
leukemias, the incidence increases as you get older. Part of the
reason for that is just accumulation of different events, toxic
exposures and events that happened to these cells that are dividing
all the time. With respect to specific risks for lymphoma, we
have identified a number of things, first of all various chemical
and toxic exposures in the environment, and we all know that there
are obviously
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more of those with processed foods and chemicals going into the
air and water, so that's a definitely a risk factor. There
are also specific risk factors with respect to infections,
particularly viral infections, that have been associated with
lymphoma and this is something that people don't normally think
about.
Chu
On that point Francine, what are some of the viruses that have been
shown to increase the risk for developing lymphoma?
Foss
We know specifically that EBV viruses are associated with the
development of B cell lymphomas and we have also identified
recently that hepatitis C can be a risk factor for the development
of lymphoma. We also know about HTLV-1, which is a virus
specifically associated in the Caribbean and Japan but also in
certain populations in the United States and that is associated
with T cell Lymphoma, and other risk factors are things like
environmental exposures and things like H. pylori, which actually
is bacteria that can colonize the stomach. We know that H.
pylori is associated with the incidence of gastric lymphomas.
Chu
EBV is Epstein-Barr virus and it is typically associated with the
development of infectious mononucleosis, is there any association
between the development of mono, which is obviously pretty common
in the general population and subsequent development of lymphoma of
any kind?
Foss
No, there really is not a specific association, but we know that
all of us are exposed to the EBV virus at some point in our
childhood. We can actually find that virus in our cells but
it remains dormant in most people. In some circumstances,
related to perhaps some defects in the immune system, the virus can
become activated and that leads me to the discussion of the
association of lymphomas with patients who are immunocompromised,
so certainly patients with HIV have a higher incidence of lymphoma
because they don't have an intact immune system. Also now that we
are using a lot of immunosuppressive drugs in various situations,
such as patients who had organ transplants, kidney, or liver, or
heart transplant they are on these medications for a long time and
they have an increased incidence of lymphoma. Also now we are
starting to use these immunosuppressive medications in other
diseases such as psoriasis and rheumatoid arthritis and we are now
starting to see an increased incidence of lymphoma in some of those
populations as well.
Chu
In that setting, when we are using immunosuppressive agents, is it
the
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duration or the extent of use that really increases the risk for developing lymphoma?
Foss
It perhaps is related to the duration, but there are other host
factors as well such as your genetic susceptibility to develop
lymphoma.
Chu
What do we know about the genetics of lymphomas? If a particular
family member was diagnosed with non Hodgkin's lymphoma, is there
then an increased risk for other family members to develop
lymphoma?
Foss
We really don't know as much about genetic risks with lymphoma as
we do about other diseases such as breast cancer, for instance,
where we identified the BRCA1 and BRCA2 genes and we can predict
with certainty that there is going to be an increased risk in other
family members. With lymphoma we do see family clustering
cases, but we really do not have specific genetic information that
we can use to screen and follow patients.
Chu
Granted there are many different types of lymphoma, but are there
any general symptoms that patients may present with at the very
beginning of the disease?
Foss
One of the problems with lymphoma is often times the patient is
asymptomatic, and patients will come to medical attention either
because they have identified a lump or lymph node or they have gone
in for a blood test for some other reason and something has been
identified. In the case where a patient is actually
symptomatic with lymphoma we identify what we call B symptoms and B
symptoms specifically would be things like fevers, weight loss,
fatigue or night sweats. So if those things occur, those
certainly would raise our index of suspicion to look for a
lymphoma.
Chu
And on a physical exam what are some of the abnormal findings that
might develop?
Foss
Well, one of the other things about lymphoma that is confusing for
patients is that not all lymphomas actually occur in lymph
nodes. Certainly if there are enlarged lymph nodes one might
feel those say in the neck or under the arms or perhaps in the
groin, but first of all many of our lymph nodes are internal and
they are not even palpable, and so the only way that we might know
that they are enlarged is if they are putting pressure on other
tissues or other organs, but generally speaking that does not
happen unless the lymph nodes are really large. As I
mentioned lymphomas can occur in areas other than lymph nodes as
well and it might occur simply as an enlargement of the
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spleen which might be symptomatic because the patient may feel
full after eating and the spleen is pressing up on the stomach or
an enlargement of the liver, and in some cases lymphoma can also
present just in the bone as bone pain or even in the skin as a skin
rash or skin nodules.
Chu
Francine, I know a lot of us will periodically have lymph nodes in
the neck region usually associated with a sore throat or upper
respiratory infection. When does one have to begin to worry
that this is more than just a simple infection?
Foss
Generally speaking I would say persistence of that lymph node over
the course of weeks, certainly if it has been a month and that
lymph node has not resolved, one should definitely seek medical
attention.
Chu
If there is a lymph node that results because of lymphoma, is that
lymph node generally tender or nontender?
Chu
I just want to make one point about that, there is a type of
lymphoma called low grade B cell lymphoma where lymph nodes can
actually be waxing and waning in the patient without medical
personnel doing anything, so you may notice the lymph node and then
it may go away by itself and then it may come back, so that kind of
pattern of waxing and waning is something that we do watch out
for. Generally speaking, if it is due to say an infection a
lymph node should resolve over the course of 3-4 weeks. It
may or may not be tender so even in the setting of having an
infection you may have a lymph node that's not tender, but
certainly if it is tender that would make us think more about
infection and less about lymphoma.
Chu
And then obviously if the suspicion is high that an individual may
have lymphoma what's the typical evaluation process that needs to
be done?
Foss
The first thing that needs to be done with any patient is
obviously to see a physician and get a biopsy. We effectively
can not make the diagnosis of cancer without seeing it under the
microscope, so we either need a piece of tissue such as a lymph
node or in some cases there may be specific findings in the blood
that would lead us to the diagnosis such as the presence of some
circulating cells that are lymphoma cells that we can detect in the
blood, but I would say by and large most patients are diagnosed
based on getting the lymph node biopsy. This can be done either by
a needle or a core of the biopsy, or preferably by a biopsy
itself. Sometimes these needles can be suggestive but not
diagnostic of lymphoma and we actually do need to go and get a
piece of the lymph node.
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Chu
This would be a surgeon generally who does this biopsy?
Foss
The needle biopsies may be done by a radiologist, but effectively
we end up with the surgeon in the end because we do need to get a
piece of tissue.
Chu
If the surgeon does the biopsies, the pathologist reviews it and
says this is consistent with lymphoma of some kind, what other
evaluations need to be done?
Foss
The pathologist is a very important person in this whole
evaluation because the whole diagnosis depends on a number of
factors that we get from the pathologist. It's not enough
just to see atypical cells any more. We really are looking
for specific genetic markers as well. The first step is to
get effective pathology and review that pathology if there are
questions about the diagnosis. The first point I would like
to make is to make the diagnosis of lymphoma and to make sure that
this is not a benign condition that has been confused with
lymphoma.
Chu
We are going to take a short break now for a medical minute. Please
stay tuned to learn more information about the evaluation and
treatment of lymphoma with my guest and co-host Dr. Francine
Foss.
Chu
Welcome back to Yale Cancer Center Answers. This is Dr. Ed
Chu and I am here in the studio with my co-host and guest expert
Dr. Francine Foss who joins me to discuss the topic of
lymphoma. Before the break, Francine, we were talking about
the biopsy procedure being done by the surgeon and the critical
role of the pathologist. For those who missed it, can you re-
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discuss the role of the pathologist and how to make the diagnosis of lymphoma?
Foss
The pathologist will be evaluating the tissue and they will be
looking at specific markers on the tumor cells or on the cells in
the tissue to try to identify if those cells are tumor cells.
Now one of the confusions with lymphoma is that these are basically
tumors of lymphocytes and in some cases these lymphocytes don't
look different under the microscope, so we really need to identify
specific genetic markers that can help us to make the diagnosis.
The thing that we look for in both T cell and B cell lymphomas is
what we call clonality, which is a rearrangement of a specific
receptor, the T cell receptor or the immunoglobulin heavy gene
receptor, which identifies the fact that all of those cells are
essentially derived from the same cell, i.e. that is a tumor as
opposed to a normal population of lymphocytes, so that's the first
thing we look for. Then we look for other specific genes that can
identify the specific subtype of lymphoma and we do have some types
of lymphoma such as mantle cell lymphomas where there is a specific
gene called Cyclin D1 that help us to identify that specific
lymphoma, and we also have T cell lymphomas such as the
ALK-positive anaplastic large-cell lymphoma where there is a
similar marker. I would like to say also for the audience
that we do actually biopsy a number of lymph nodes that are called
pseudolymphoma that are not actually lymphoma and we believe that
these are a benign proliferation of cells that don't actually go on
to lead to lymphoma, so not all of the patients that are referred
to me as a lymphoma doctor actually have lymphoma.
Chu
In 2010 the current standard of care as part of the evaluation
process is for all of these genetic tests to be done on that biopsy
specimen.
Foss
Exactly there are many, many tests that are done in addition to
looking under the microscope.
Chu
So once all of those tests are done and you have a diagnosis, the
definitive hard diagnosis of lymphoma, what's the next step?
Foss
The next important thing to do is what we call staging, and that
is to see how extensive the disease is and we do that by obtaining
either CAT scans or PET scans and oftentimes also by getting a bone
marrow biopsy to see if any of the cells are in the bone
marrow.
Chu
What are the different treatment options that are available to you
now as a
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medical oncologist?
Foss
There are many, many treatment options for lymphoma and they run
the gamut from doing nothing, which is watching and waiting which
we do in patients with low grade B cell lymphoma, to doing
radiation of a single lymph node area to doing chemotherapy or
possibly even aggressive chemotherapy and a bone marrow
transplant. It really depends on what kind of lymphoma you
have and how extensive that lymphoma has spread at the time of
diagnosis.
Chu
Some of our listeners out there may be scratching their heads and
saying, you have someone with lymphoma, you say low grade lymphoma
and one of the options may be to do nothing?
Foss
This has really been paradigmatic for a lot of us as physicians as
well, because when you and I were back at the National Cancer
Institute, a very large and pivotal clinical trial was done for
patients with low-grade B cell lymphoma, and those patients were
randomized to either receive a very aggressive chemotherapy regimen
along with radiation to all of their lymph nodes in an attempt to
cure them. In the other arm of the study, patient's got no
treatment and they were followed for their disease and if they did
develop symptoms they may have had some very mild chemotherapy or
very limited radiation. Everybody at the time we initiated
that study thought that the patients on the aggressive arm would do
better and live longer, and what ended up happening at the end of
the day is that there was absolutely no difference in survival, and
so that has really changed our thinking about low grade lymphoma
and in fact, the way we approach low grade lymphoma now is to
either watch and wait the patient if they have no symptoms or if
they do have symptoms to treat them with biological therapies
rather than chemotherapy. I am referring specifically to the
monoclonal antibody rituximab which targets CD 20 on the surface of
those cells.
Chu
And that antibody therapy really has revolutionized the treatment
of lymphoma.
Foss
The major step forward that we made in the last 20 years with
lymphoma has been the implementation of that monoclonal antibody
rituximab, not only by itself for patients with low grade lymphoma,
but also in combination with chemotherapy as a first line therapy
for patients with diffuse large B cell lymphoma where we have were
shown that we can cure a significantly larger number of patients by
combining the antibody with the chemotherapy, and then the third
thing that has really changed our treatment is that we have
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been able to actually link that antibody to various
radioisotypes to create
radioimmunotherapy, which has also been very effective as a
treatment for patients.
Chu
This biologic therapy Rituxan, does it have any side effects?
Foss
The nice thing about rituximab is that there are very few side
effects other than the first dose where patients might get chills
or fever or a reaction to the infusion of the medication, but
generally speaking after that patients can get this medication for
months or even years without having any significant side effects
from it.
Chu
It's really very different than the traditional chemotherapy like
the standard cancer agents that you and I have been so accustomed
to for the last 20-25 years?
Foss
Exactly, and what's really important when you think about this as
a patient is you really need to know what the goals of therapy are
for your specific type of lymphoma, so for instance, if you have
diffuse large B cell lymphoma which is an aggressive disease, you
would not be treated just with this antibody therapy; you would
need chemotherapy. And if you have low-grade lymphoma and
it's the type of low-grade lymphoma that can be followed or treated
conservatively, then you do not need chemotherapy.
Chu
What's really remarkable about the treatment of lymphoma when you
look at just say the last 5-10 years is there have been dramatic
advances in the number of new treatments, new drug regimens, and
new agents that have been approved to treat lymphoma.
Foss
That's very true and I think this is a very exciting time to
actually be in the field of lymphoma. Rituximab, we
mentioned, was a huge step forward, but if you look over the last
3-4 years, particularly over the last year, there have actually
been 3 or 4 drugs approved for lymphoma. One of the drugs
that was approved is bendamustine and that was actually approved a
couple of years ago and the thing about bendamustine is that
recently it was used with rituximab and compared to rituximab plus
CHOP, which is aggressive chemotherapy, it showed that the results
were the same, and the nice thing about bendamustine is it does not
have the side effects such as hair loss and other side effects
associated with chemo, so that was a huge step forward. We
also had another monoclonal antibody called ofatumumab
approved. This was actually approved for CLL, chronic
lymphocytic leukemia, but it also targets the CD 20 that rituximab
targets so I think we are going to
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see that used also in lymphoma. We have also had two drugs
approved for
T cell lymphoma and these in fact are really important drugs
because we don't have good therapies for T cell lymphoma. One
of these drugs is pralatrexate and the other drug is romidepsin,
which is a histone deacetylase inhibitor, another novel biological
strategy for treating lymphomas.
Chu
Francine, obviously you are a world expert in the treatment of all
lymphomas, but I know that you have had a particular interest over
the years in the treatment and evaluation of patients with T cell
lymphomas and there also have been pretty significant advances in
addition to the two drugs that you just mentioned.
Foss
The T cell lymphomas have generally been the forgotten lymphomas
because T cell lymphoma is about 10 to 15 percent of all lymphomas,
and the number of cases is about 8-9 thousand per year in the
United States. There really has not been as much research on
T cell lymphoma because we haven't really understood the biology,
so only recently, over the last 3 or 4 years, have we been able to
do molecular profiling of these tumors and identify specific
subtypes of T cell lymphoma and we have also now started to tailor
our treatments for these specific subtypes.
Chu
We have talked about chemotherapy and biologic targeted therapy.
When would you consider the role of bone marrow transplantation or
stem cell transplantation in treating a patient with lymphoma?
Foss
Stem cell transplantation is a very important treatment for
lymphoma, and in fact, if you look at the indications for stem cell
transplant in the United States, leukemia is obviously number one,
but non Hodgkin's lymphoma is the second largest and the number of
transplants done for non Hodgkin's lymphoma is increasing.
There are basically two different types of transplant; the
autologous transplant and the allogeneic. And the autologous
is when you give yourself back your own cells and that's being used
now for patients with diffuse large B cell lymphoma who have
relapsed disease. It's also being used for patients with aggressive
T cell lymphomas whereas the allogeneic transplants, or getting
cells from somebody else, is used primarily for lymphoma patients
who have either a very aggressive histology, or for those patients
who have already failed an autologous stem cell transplant, and
fortunately for us, because of advances in transplantation we are
now able to transplant patients even in their 70s.
Chu
One question that always comes up with the autologous transplant
when you are giving back the patient's own bone marrow is whether
or not there is the
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possibility that there may be contamination with lymphoma. Is
there
anything that's done to try to screen for that and to make sure
that there are no lymphomas cells that are being infused back into
the patient?
Foss
This is an important question Ed, and in fact, the primary risk
with the autologous transplant is relapse, so early on there was
some relatively primitive strategies to try to so called 'purge'
those stem cells of the tumor cells, but now that we have agents
like rituximab and the radiolabeled antibodies such as Zevalin and
Bexxar what we can do is administer these therapies directly to the
patient and thereby purge the patient of tumor cells before we
harvest the stem cells, and this is proving to be a very effective
strategy for patients with B cell lymphoma. Unfortunately we do not
have really great ways of doing that yet in patients with T cell
lymphoma.
Chu
With respect to allogeneic transplantation, what are the main side
effects and complications from that procedure?
Foss
That really depends on the type of allogeneic transplant. We used
to do what we called ablative transplants where we gave very high
doses of radiation and chemotherapy and there was lots of toxicity
just associated with the conditioning regiment, and now we know
that we can actually do what we called reduced intensity, or mini
transplants, where we give very little chemotherapy and virtually
no radiation therapy, thereby not exposing our patients to a lot of
toxicity. Now the major complication of allogeneic transplant is
graft-versus-host disease, which is when the new cells basically
reject the body and that can cause diarrhea, liver problems, and
skin rash; that's a major toxicity. We always worry obviously about
the infectious complication as well. Generally speaking
though we have got very good supportive care and new approaches for
graft-versus-host disease and so the frequency of these
complications is decreasing.
Chu
You really have been one of the leaders and the pioneers in trying
to develop new agents, new treatment strategies, for lymphoma,
maybe you can tell our listeners out there what some of the
interesting clinical trials and clinical research that your group
at Yale Cancer Center are currently conducting?
Foss
One of the things that we recently completed, which I think is
really a important clinical trial, is the combination of a targeted
T cell agent such as ONTAK with chemotherapy for patients with
aggressive T cell lymphoma, and by combining these strategies we
have been able to increase the complete response rate to about 90%,
and that is compared to 50% without
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the targeted agent. I think that's an important strategy,
and the other thing we are working on is an ongoing clinical trial
now to explore the role of the histone deacetylase inhibitors
combined with various chemotherapy agents and also the use of novel
monoclonal antibodies and other novel targeting strategies.
We are also looking at signal transduction pathways and we have a
clinical trial with Sorafenib, which is a small molecule inhibitor
of one of these pathways and I think that's going to be an
important advance as well.
Chu
If anyone listening out there is interested in hearing more or
learning more information about what's going on with your
hematology malignancies group, how can they get information?
Foss
The information is available on the Yale Cancer Center website
where we have a list of all the clinical trials that are
available.
Chu
Great, well Francine the time has gone fast, as always it was great
having you as a guest on the show and I look forward to next week
when you resume your role as co-host of the show. Until next
week, this is Dr. Ed Chu from Yale Cancer Center wishing you a safe
and healthy week.
If you have questions or would like to share your comments, visit yalecancercenter.org, where you can also subscribe to our podcast and find written transcripts of past programs. I am Bruce Barber and you are listening to the WNPR Health Forum on the Connecticut Public Broadcasting Network.