Thank you for joining for the Lymphoid Disorders lecture of the Hematology and
Oncology Unit for the General Medicine course. Please be sure you have your
study guide so you can complete that as you go through this lecture.
The learning objectives for this lecture are listed below. Please do make sure you are
looking through these so you're ready for the exam. Before we talk about
lymphoid disorders, its first important to discuss hematopoietic stem cells. In
our previous lecture where we were discussing myeloid disorders we were
talking about the myeloid cell lines but this time we will be talking about the
lymphoid cell lines. So you have your hematopoietic stem cell which will
develop into your lymphoid progenitor, so we'll be talking about this grouping of
cells here (circle). Specifically for these lectures we're gonna be focusing on the
lymphocytes and you'll also see of course that our B lymphocytes will
develop into our plasma cells so when we talk about the plasma cell disorders.
Realize that these are also still B lymphocyte disorders.
So here is another view of the lymphoid disorders, not looking from hematopoietic stem cell
point of view, but just hematopoietic malignancies in general and the
area that we'll be discussing today are the lymphoid disorders. These will be
divided into two big areas- the acute lymphoid leukemia and then all the chronic
lymphoid disorders.
So just a reminder from the previous lecture about leukemias. Leukemia as our malignancies the progenitor cells so these can be myeloid
or lymphoid cell lines so either one of those and the name will tell you which
line it's coming from. Remember that though progenitor cells are the blasts
or the immature cells and when you have a leukemia they start in cumulating in
the bone marrow eventually the bone marrow fills up with
these immature blasts and you start having them spill into the peripheral
blood and eventually as they start filling the peripheral blood as well you will
start having them accumulate in other tissues of the body. Remember that the
blast cells are non-functional cells and because they eventually start taking up
the bone marrow they can lead to pancytopenias because you start losing
your normal cells that should be there. Again another slide from the previous
lecture but just a review of the signs and symptoms of leukemias- the big
being fevers, chills, and night sweats; weakness or fatigue; infections related
to the bone marrow being overtaken by the bad blast cells and you are losing
some of your good original cells; weight loss can be a big symptom of this;
lymphadenopathy can also develop as well as hepatosplenomegaly because of
the blast cells starting to take over the other organs as they start moving
from the bone marrow they start taking over the blood and then eventually they
start depositing and the other organs. Peetechia and purpura epistaxis are
related to again some of those cells the bad cells or blast cells start taking
over the bone marrow- we lose some of our good cells so we have problems with the
development of platelets, as well and bone tenderness or pain develops because
as those blast cells start coming into the marrow and taking over the marrow.
There can be pain that develops as a result as well.
So the first leukemia we'll talk about for this lecture will be the acute lymphoblastic leukemia, also
known as ALL. ALL is a leukemia of lymphoid origin specifically the B and T
cells and what happens is you have the immature or blast cells for the B or T
cells that start proliferating and they eventually take over the healthy bone
marrow. It's important for ALL to remember that most acute leukemias in
children (about 80%) will be in ALL. Especially with the highest incidence
between the ages of 3 to 7, so if you have an exam question or a case study
that has a young child who has this the picture for leukemia, specifically an
acute leukemia you should be thinking first and foremost that it's ALL. Also
to note in adults who have acute leukemia is it only counts for about 20%
in adults so it's helpful because the 80 and 20 match up even though they're not
necessarily related. The treatment for ALL is based on the patient's age and
several different risk factors. The typical treatment will use a combination
chemotherapy and this usually involves daunarubicin,vincristine prednisone
and asparaginse and remission with this
treatment is in about 90% of patients. if the patient does have a Philadelphia
chromosome for a ALL, which is not typical but is a possibly bad indicator
or poor prognostic indicator in these cases. It is helpful to add to that
combination that dasatinib, which is a tyrosine kinase inhibitor and it will
help somewhat for these patients. If the patient is above the age of 60 dasatinib
plus prednisone is also used. and if you have a chronic remission and you need to
do an induction phase for these patients it's very important to make sure that
there is CNS prophylaxis is done and what this involves is intrathecal and/or
intracranial chemotherapy- so the chemotherapy is put right into the spine
or into the cranial region. And that is to help prevent any other issues with
malignant meningeal leukemias. They may also have some irradiation done at that point
as well. And some other treatments that might be done, so again possibly some
chemotherapies for induction or possibly stem cell transplants.
Prognostic indicators for ALL. It is important to look at different
prognostics for ALL to decide and dictate the treatment. Some of the good
prognostic indicators are no adverse cytogenetics- so no bad gene
abnormalities- the ones that I want you to remember for the good ones for ALL
are patients who are younger than 30 years of age is a very good prognosis
and if they have a white blood cell count less than 3000 at their
presentation that is also a good prognostic. Another prognostic indicator
that is helpful is if patients are doing about four weeks or so of chemotherapy
and they've reached complete remission, by that point that is a very good
prognosis. There is no specific indicators for intermediate prognostics-
it's kind of finding the balance of the good and the poor but there are some
or indicators that I wanted to discuss. So some of the adverse cytogenetics
would be especially this translocation of 9 and 22, which is again that
Philadelphia chromosome as you remember. In our previous lecture we talked about
if you have the Philadelphia chromosome in ALL or AML both of those are
considered a poor prognostic indicator. As well if patients are older than age
of 60 then they have a much poorer prognosis. So that one I want you to
remember. And finally also remember that if they have a high white blood cell
count, that is higher than a hundred thousand at presentation, that is a
concern for a poor prognosis. Also patients who do not reach remission
within that four-week period after chemotherapy started also have a poorer
prognosis.
Next we'll discuss chronic lymphocytic leukemia or CLL.
Chronic lymphocytic leukemia or CLL is also a clonal malignancy of lymphocytes so this
can be both B cells or T cells and this is typically seen in older adults,
especially over the age of 70. On diagnosis you will of course see the
increased circulating lymphocytes- and another important word to know for CLL
would be this smudge cells, which show up on peripheral smear. And basically these
smudge cells are lymphocytes but they're extremely fragile and so what ends up
happening (as you can see a couple examples here) you have these cells that
are kind of being broken up or smudged on the slide. You also will see with CLL
that their lymphocytes start getting into the lymph nodes as well so it's a
characteristic for this that's good to make sure you remember. The staging for
CLL is done by the Rai and Binet System and this is not a slide that you
have to memorize- it's just there more for your information. It's helpful to
remember that there is staging that is done for this type of leukemia as well
and it's helpful to know that the staging is based off of (some of its) the
lymphadenopathy, if there is any spleen or liver involvement, looking at
hemoglobin and then platelets. And again you can see some of the similarities it
still looks at hemoglobin and platelets in the Binet staging but it doesn't
necessarily look at these other two prognosticators- here the lymphadenoapthy
or the hepatosplenomegaly.
The treatment of CLL is based off the Rai stages. As you saw on the previous slide you can see below stage zero would
require no treatment (these patients are monitored, of course if these patients
progress into some of the other stages- the intermediate stages, the higher
stages, they do require treatment). At those times and typically at stage zero
the median survival is greater than ten years. If a patient is in the
intermediate stages , so specifically stage one and stage two, most of them
will receive some therapy and if they are in a higher stage they will most
definitely receive therapy. So stage three and four and the therapies are
listed on the other side of this slide. So you can see chemotherapy is the
principal treatment. The drugs involved would be through fludarabine plus
rituximab as well as possibly cyclophosphamide. Another option would be
would be chlorambucil. If they have refractory CLL and they don't respond to
the first sets of chemotherapy, there are some other possible treatments alemtuzimab
is a possibility and also stem cell transplantation is a possibility but do
you remember that the older the patient is the less likely they're going to do
well with transplants with stem cells. Allogenic stem cell transplants are
potentially curative and are recommended because if you do an autologous stem
cell transplant you run the risk of still having contaminants in the
patient's own stem cells that are harvested- but again remember that there
is a lot of mortality related to this, especially as patients get older.
Now we'll discuss lymphomas. Lymphomas are a hematologic malignancy of the
lymphoid tissues and this involves, especially the lymphocytes but it's
usually characterized as B cells T cells and sometimes NK cells. Lymphomas are
named lymphomas because this sight of the disease is the lymph nodes,
however lymphomas can also invade other lymphoid tissues- those would include
things such as the liver, the spleen, the Peyer's patches of the intestines,
portions of the skin, as well as invading eventually invading the bone marrow.
Lymphomas are typically divided inHodgkin and Non-Hodgkin lymphomas. About
85% of Non-Hodgkin lymphomas are B-cell origin and Hodgkin lymphoma are
all of B-cell origin.
Risk factors for lymphomas. There are many risk factors for lymphomas but one of the
most important ones to remember is viral infections, specifically the Epstein Barr virus.
The Epstein Barr Barr virus is especially implicated in Hodgkin lymphoma. Bacterial infections could be
responsible for lymphomas as well, especially H. pylori, which is related to
gastric associated lymphomas also called GALT. We'll discuss that a little bit later.
There can be different immune issues that could lead to lymphomas.
There are some congenital syndromes as well. Lymphomas could be acquired from
other treatments, such as stem cell transplants. It could be related aging,
autommune, and also again acquired from infections, like HIV and also exposures
to things such as herbisides and pesticides can put people at risk for lymphoma.
The diagnosis of lymphoma is ultimately made by a lymph node biopsy
and the preference for this biopsy would be the excisional biopsy- this is the
gold standard method for biopsy. It is possible to complete a fine needle
aspiration also called an FNA and this procedure is less invasive and it may be
necessary if the node is in a place that is not easily excised. It could also
be because the patient is not able to tolerate a surgery but could have a
needle aspiration which doesn't require the same level of anesthesia to have
this done. It also could be related to the surgeon's preference but ultimately a
excisional biopsy of the lymph node is preferred and it this is because it
gives you a more accurate diagnosis. Once you have that lymph node tissue you can
send that for pathology to run the testing for looking at Reed-Sternberg
cells. If you do have those Reed-Sternberg cells present, you would be
diagnosed with a Hodgkin lymphoma and of course, if there are not Reed-Sternberg
cells then it is a Non-Hodgkin lymphoma. Those samples will also be sent for flow
cytometry and cytogenetics to get further prognostics to decide on the patient's
treatment.
Non-Hodgkin Lymphoma. Most Non-Hodgkin lymphomas will present with a painless lymphadenopathy and these are typically seen in the
cervical, axillary, or groin regions. Patients may also complain of fatigue or
rashes and about half of patients will also have "B symptoms" and these are
constitutional symptoms which can be fever, night sweats, and or weight loss
(and this weight loss would be greater than 10% of the patient's body weight
over less than a six-month period). Non-Hodgkin lymphomas are also put
into a grading system you can have indolent lymphomas, intermediate grade
lymphomas, and high-grade lymphomas. The indolent lymphomas with "indolent" meaning
"slow growing, painless, or not problematic," typically have that painless
lymphadenopathy whether it be one isolated lymph node or
multiple lymph nodes. In the indolent lymphomas you will see
well-differentiated cells meaning they are very close to normal cells. Typically in
this grading patients have few symptoms and often in these cases it is less
likely to see these patients present early. They may present later once they
move up to other grades and these patients will however progress
slowly- an example of one of the indolent lymphomas would be a follicular lymphoma,
which is the most common type of indolent Non-Hodgkin lymphoma.
Intermediate or high-grade lymphomas will also present with lymphadenopathhy
often and is painless, however as a patient moves to higher grades they will
have more lymphadenopathy and larger lymphadenopathy and they are
more likely to have pain because of the lymph nodes that are enlarged pushing on
underlying structures. In these grades you can have poorly differentiated or
are very undifferentiated cells meaning that they are very abnormal cells
compared to the normal cell that they should be. You aree more likely to see the
B symptoms in these patients, so again those fevers, night sweats, and weight
loss and patients in the intermediate and high grade lymphomas tend to
progress more quickly. An example of an intermediate grade lymphoma is a diffuse
large B-cell lymphoma, which is the most common type of lymphoma. A high-grade
lymphoma would be something like the Burkett's lymphoma ,which is very rare
but very aggressive. Also, another rare and usually higher grade lymphoma is the
T-cell lymphoma is there often presenting with a continuous
manifestation which we'll talk about in a little bit.
When staging Non-Hodgkin lymphoma it's important to take a very good history and physical. Also, be sure
that you are documenting any of the B symptoms. Laboratory evaluation will
include a CBC and most likely a peripheral smear, as well liver function
testing, uric acid, and calcium testing Also recommended patients should
have a chest x-ray as well as CT scans of the abdomen pelvis and the chest as
well to look for any other node involvement patients. Also will receive a
bone marrow biopsy and possibly a lumbar puncture depending on the type of
Non-Hodgkin lymphoma they are diagnosed with. Other scans can be done,
especially things like PET scans to look for cancer
involvement in other areas of the body, but ultimately please remember that the
lymph node biopsy is your most important test for getting the correct diagnosis!
The staging for the lymphomas are listed below= let's go through a couple of these
right now. Stage I will involve a single group of
lymph nodes and notice it says a group meaning you could have a cervical group.
you could have a supraclavicular group but it is a group of lymph nodes not just a single
node or possibly you could have a lymphoid structure. So this could be the
spleen or other lympg organs involved. In Stage II you will have two or more
lymph node groups involved but very importantly they are on the same side of
the diaphragm and we'll look at some images on the next slide and that will
make a little more sense. Stage III will be the involvement of lymph node groups on
both sides of the diaphragm and that means obviously you are going have at
least two groups involved- dp you are going to be past that stage two- but because you
have one group on one side of the diaphragm and one group on the other
side of the diaphragm, that would put you in Stage III now if you have two groups on
the one side of the diaphragm and one group on the other that still puts you
into Stage III. Stage IV will also involve some extranodal sites and will
get the designation of "E," so those would be common places, such as the spleen,
liver, or the bone marrow also having involvement. Finally, you will have the A
and B symptoms noted, so if there are a presence of B symptoms you'll give it a
"B," if there's no "B" symptoms reported by the patient it will receive an "A." Also,
you will see this "X" designation for bulky disease meaning that they have pretty
big lymph nodes involved, usually it is greater than 10 centimeters and of
course you could also see some changes in the mediastinum where you have a node
and that would help with that diagnosis as well.
Here is the photographic representations of the lymphoma staging, so for stage I you will see that this
patient has just one group of lymph nodes involved
that would qualify for stage I and stageII there are two or more groups of
lymph nodes involved, but they are all on one side of the diaphragm. So here's the
diaphragm here and here are my two groups that are involved so for this
case. If you wanted to for example take out these groups they are no longer there
and I had lymph node involvement on both sides of the groin, for example, I would
have one here, one here, they're both on the same side of diaphragm this would
still qualify as stage II. In stage III disease you have groups on both sides of
the diaphragm and in stage IV not only are there multiple groups involved but
we also have organ involvement or other lymphoid involvement. So that would be
the spleen, the liver, and you can see here they also have bone marrow
involvement in this case.
Just to review the lymphoma of B symptom again fevers- and a lot of times with these fevers you will see them waxing and waning and
these can sometimes be the reason for a fever of unknown origin, so you have a
patient who's comes in there having fevers and we're not able to find a
cause- there's no other infection that's apparent,
so fever of unknown origin you should always have a lymphoma on a differential
diagnosis. Sometimes these waxing and waning fevers you will see them referred
to as a Pel-Ebstein fever, so they have periods of fever as well as
afebrile periods. For the night sweats, these are considered drenching night
sweats, meaning that the patient has to wake up and change their night clothing
or their bed linens because of the amount of sweating. And again that
unintentional weight loss greater than 10 percent of weight and this is over
less than a six-month period. Remember if the B symptoms are present, then you
would give the staging of B after the stage and if they are absent the staging
will receive an A.
One of the most important medications for treating Non-Hodgkin lymphoma is rituximab.
Rituximab is a monoclonal antibody which is directed against CD20, so this is an anti-CD20 medication and CD20 is
seen on B-lymphocytes. So any of your B lymphomas, which are about 85% of
Non-Hodgkin lymphomas, are going to be treated with this medication. They also
are put in to combo chemotherapy, so you can see our rituximab is here for the
combos that is where the "R"comes from for both of these and then the other
chemotherapeutics are put in there. So you often hear these referred
to as an R-CHOP chemo or an R-CVP chemo.
Now let's discuss some of the treatments for specific types of lymphoma. First
we will talk about follicular lymphoma, which again is one of those indolent
lymphomas. Remember that it often does not require treatment- its indolent, its
early and is progressing slowly- so it won't need treatment until later.
However, if the patient has some specific symptoms, then they may be treated and
these are listed below: it would include progression of their
disease or bulky disease and that would mean in this case greater than a five
centimeter mass, if they have any other organ compromised, then that would be an
indication for treating them, if these patients do have the B symptoms they
should be treated as a higher staging, also if they have any other symptoms of
extranodal involvement (meaning that other organs are involved with some of
the infiltration of the abnormal cells- so these will be pleural effusions or
cytopenias due to bone marrow involvement or involvement of the spleen),
then they should also be treated ,and they will again receive this rituximab
with some sort of combo therapy, so that would be either R-CHOP therapy or
R-CVP therapy. Diffuse Large B-cell lymphoma is again an intermediate grade
;ymphoma. it is typically treated with the rituximab treatment because again it
is a B-cell lymphoma and it is going to also have the combination therapy so
it's going to be either R-CHOP or R-CVP treatment with chemotherapy. It
is important to remember that if these patients do relapse that they can be
treated with a stem cell transplant, but often this is considered a very poor
prognosis for these patients.
For the treatment of Burkitt cell lymphoma or Burkitt lymphoma, remember this is not a very aggressive,
very high grade lymphoma, it's commonly related to HIV infections and is
especially endemic to East Africa as it's very common there. And this is a
type of lymphoma that is pretty responsive to the R-CHOP therapy for
chemotherapy but these patients are also going to need CNS prophylaxis. So they're
also going to need intrathecal and intracranial treatments of the chemotherapeutic.
T-cell lymphoma. So remember that most non-Hodgkin lymphomas are
going to be B-cell lymphomas (about 85%), the rest of them will be T-cell
lymphomas and these are very very aggressive lymphomas. They do not respond
well to chemotherapy and of course because their T-cell, they will not have
a response to rituximab, which is against the CD20 which is on the b-cell.
Typically these are divided into the type of mucosal-associated lymphomas
and the most common ones will be cutaneous T-cell lymphoma, which you can
see here in a photo. So you can see this patient presents with erythroderma,
which is deposits of the T-cells into the skin so this is a SALT, a skin-
associated lymphoma. You can have gastric lymphomas, so the
GALT lymphomas, which patients need to be treated for H. pylori and you can also
have the enteropathy- associated T-cell lymphomas and these involve infiltration
of the Peyer's patches of the small intestine.
Hodgkin Lymphoma or Hodgkin's Disease.
Hodgkin lymphoma has a bimodal age distribution meaning that there is peaks in two different age groups- the first age group is 20 to 30
years of age and the second age group is patients over the age of 50.
Like Non-Hodgkin lymphoma, patients with Hodgkin lymphoma also present with a
painless lymphadenopathy, as well they may present with the B
symptoms of fever, night sweats, and or weight loss. Other clinical features that
you can see in Hodgkin lymphoma would it be unexplained itching, cerebellar
degradation or hemolytic anemia. And again like
Non-Hodgkin lymphoma, patients with Hodgkin lymphoma are ultimately
diagnosed by a lymph node biopsy. Most importantly they will possess the
Reed-Sternberg cell, which you can see here- this cell that is indicated on the slide
here.
The studies for the staging of Hodgkin lymphoma are the same as Non-Hodgkin lymphoma. Again a good history and physical documentation of
any B symptoms. Laboratory testing- CBC, probably a peripheral smear, as well
liver function testing, as well as uric acid and calcium testing, getting your
imaging of your chest through radiographs, as well as abdomen and
pelvis through CT, a bone marrow biopsy, and PET scanning- but ultimately remember
that that lymph node biopsy is the most important test you will need to get.
The staging for Hodgkin lymphoma is the same as Non-Hodgkin lymphoma so just be
sure that you are familiar with the staging for both of these and realize
that they are the same. Again here is the imaging of the staging and photographic
representation and again the B symptoms will be used in that grading as well.
There are some important considerations for the staging of Hodgkin lymphoma. It
is more common to see that patients with Hodgkin lymphoma have a tendency to
have a single lymph node group that starts at their disease and then it
spreads in a very typical pattern to the next group. So it's very important to
get the correct staging because it has a very big influence on the treatment of
Hodgkin lymphoma patients more so than you would see with Non-Hodgkin lymphoma.
Most Hodgkin lymphoma patients do not have the B-cell markers present
(so like CD20 as we saw in some of the other cases)- instead they have other
markers such as CD15 which is a myeloid cell line adhesion molecule,
CD30 which is a TNF alpha receptor, and CD45 which is a leukocyte antigen. There is
one variant of Hodgkin lymphoma that does have a CD20 positive variation.
It iss also important to make sure you look at Epstein-Barr virus and its
implications in Hodgkins lymphoma and you'll often see that they are Epstein-Barr virus positive.
There are several combination chemotherapies that can be used in the treatment of Hodgkin lymphoma.
The gold standard for these chemotherapy combinations is the ABVD, which is a
adriamycin, bleomycin, vinblastine, and dacarbazine. There are some other options,
such as escalated BEACOPP or Stanford V. You can see here that stage 1 or stage 2
disease will be treated with ABVD- the gold standard treatment and the
presence of the B symptoms will dictate whether or not the patient has radiation.
So important things to remember for this section is either way they are going to
get the AVBD but know that if the B symptoms are present that radiation will
be given. As well if you have a patient in stage 3 or 4 or a patient with stage
2 that has very bulky disease (meaning very large infiltration of the lymph
nodes) they will either receive the AVBD or the escalated BEACOPP plus or
minus radiation so they may have radiation they may not or there's the
possibility that they could receive the Stanford V but the Stanford V definitely
needs that radiation. So make sure you can distinguish that they can get any of
these three treatments for stage three or four but the only one that requires
the radiation is this this Stanford V.
The prognosis of Hodgkin lymphoma depends on the staging. Stages 1 and 2 will have approximately a 10-year
survival greater than 90 percent. stage 3B or stage 4 patients will have a
10-year survival of about 50 to 60 percent. And the patients in between
stages so Stage 1B and 2B as well as 3A will have a 10-year survival between
that 60 to 90%. If patients have recurrent disease
they are often treated with a high-dose chemotherapy and may also have stem cell
transplantation about 35 to 50 percent chance of cure with that if the disease
is also responsive to the chemotherapy. Patients who have a poor prognosis in
Hodgkin lymphoma include older patients, patients with bulky disease
(remember that's again those very big greater than 10 centimeter lymph nodes),
and if they have lymphocyte depletion or other mixed cellular types of Hodgkin
lymphoma they can also have a poor prognosis.
Plasma cell disorders. Plasma cell disorders are divided into multiple myeloma and Waldenstrom's
macroglobulinemia, which is also called lymphoplasmacytic lymphoma.
Multiple myeloma. Multiple myeloma is a hematologic malignancy of the plasma
cells. Plasma cells are the mature form of a B-cell and remember that these are
cells that make a single antibody. In multiple myeloma there is a defect that
occurs in these plasma cells which causes them to let off fragments of
immunoglobulin. Immunoglobulin is normally consisting of two heavy chains
and two light chains and in this case there are portions of the light chain
that is being sent out into the system- this is also referred to as M proteins.
The major symptoms at diagnosis for patients with multiple myeloma are bone
pain, fatigue, weight loss, and paresthesias. Some of the clinical
features seen in multiple myeloma include anemia, which is often normocytic
and normochromic. The anemia is caused by the replacement of the healthy marrow
with abnormal plasma cells. As these plasma cells increase the abnormal
plasma cells will start invading the bone marrow and taking up the space of
the other progenitor cells. You will see multiple monoclonal or M proteins in
patients. Also you will have increases in plasma cells in the bone
marrow and remember these are abnormal plasma cells, so they start invading the
marrow as well. One of the other symptoms that you will see in patients with
multiple myeloma are lytic bone lesions, which are seen on radiographs.The lytic
lesions are due to abnormal plasma cells that start crowding out the good cells
in the bone marrow. This also causes an increase in osteoclast activity and that
will lead to lesions because there's resorption of the bone as a result of
this. So you will see pathologic fractures in these patients as well
because of the bone breakdown there can be hypercalcemia patients with multiple
myeloma will also have renal failure and that is because the circulating M
proteins begin to deposit in the kidneys and become nephrotoxic to the kidney. In
this case you'll see an elevation in the serum creatinine. Patients with multiple
myeloma also are at an increased risk for infection this is because there is a
decrease in the humoral immunity which is due to the loss of the normal plasma cells.
The workup for a patient with multiple myeloma starts with a good history and physical exam, blood workup for this patient will include a CBC, as
well as a peripheral smear- and on the peripheral smear you may see below RBCs
and this is a stacking of the red blood cells which is due to proteins in the
blood and we'll talk about that a little bit more with the next syndrome. We will
discuss it is also important to get a BUN and creatinine as well as
electrolytes, calcium, albumin, LDH. One test that is helpful is a quantitative
immunoglobulin and light-chain assay to look at some of the changes in the
amount of immunoglobulin in the blood. And the most important test would be a
serum protein electrophoresis, specifically looking for M spikes which
are a result as a result of the increased M proteins related to the
increased light chains in the blood. You'll see here on this image here that
the electrophoresis has that M spike
that has occurred. There is also some testing for the urine
and the urine will show these what is called Bence Jones proteins and these
are again related to the M proteins or the M spikes you can do an electrophoresis
of the urine as well, which will show the M spikes. And the other important test
to get is a skeletal survey and this is a series of radiographs or x-rays which
will show the lytic lesions. It is also important to have a bone marrow biopsy
so you can run testing for cytogenetics.
There are three criteria for the diagnostic criteria of multiple myeloma and this would include the presence of
a serum or urine monoclonal protein (so again testing that on the
electrophoresis is that best way to obtain that ), the presence of a clonal
plasma cell in the bone marrow (so you will need that bone marrow biopsy to get
that diagnosis and this needs to be more than 10%, you also could have the
presence of a plasmacytoma that could take place with this criteria and a
plasmacytoma is either a bone or a soft tissue mass of abnormal monoclonal
plasma cells)- the third criteria is a presence of end organ damage that is
related to some sort of plasma cell abnormality and this is done by the CRAB
acronym. And that will be "C" which is for hypercalcemia, "R" which is for the renal
failure, "A" which is anemia, and "B" which is those bone lesions which are considered
lytic lesions. So lytic bone lesions and you can see here on the radiograph here
there are lots of different lytic lesions of the skull in this patient.
The diagnostic criteria for atypical myelomas. I like to think of the atypical
myelomas as as the syndromes kind of leading up to multiple myeloma- these
will include smoldering multiple myeloma or SMM and monoclonal gammopathy of
undetermined significance or MGUS. For smoldering multiple myeloma
I kind of think of this as the syndrome that has the testing that is positive
for multiple myeloma but it doesn't meet the last requirement, so they'll have the
serum monoclonal proteins and those will be greater than or equal to the three
grams per deciliter, as well they will have the plasma cell issues in the bone
marrow greater than 10% or equal to 10%, but they do not have those end organ
damage issues due the plasma cells- so that basically is saying that they don't
have that CRAB acronym that we talked about- so they do not have hypercalcemia,
they do not have renal failure, they do not have anemia. and they do not have any
lytic bone lesions. In the case of monoclonal gammopathy of undetermined
significance, they will have serum monoclonal proteins but they are less
than the required 3 grams per deciliter, they do have plasma cells in their bone
marrow but they are less than the 10% that is required and again they do not
have those and organ damage issues.
Treatment of Myeloma. Chemotherapy is currently the mainstay of treatment for
patients with multiple myeloma and these can include any of these 3 types of
treatments or possibly them in combination- dexamethasone would be one
option, the other option would be either lenalidomide or pomalidomide, and another
option would be bortezomib or carfilzomib. Patients with myeloma may
also be treated with radiotherapy and this is for their bone pain. It is a
palliative treatment- it could also be used for getting rid of a tumor that is
at the site of a fracture. If you have a patient with MGUS or SMM, they will be
observed, however if they do progress to multiple myeloma they will require
treatment. Some other treatment options include managing the hypercalcemia that
is seen due to the renal issues, as well as the bone breakdown. Also vertebral
collapse should be addressed with either vertebroplasty or kyphoplasty or
possibly using bisphosphonates to try and reduce the pathologic fractures
and to also try and treat some of the hypercalcemia issues. Typical survival
for patients when they progress to the point of myeloma which at the level of
multiple myeloma will be approximately five years and stem cell transplant is
being considered for patients but it's still considered experimental.
Waldenstrom's macroglobulinemia, also known as lymphoplasmacytic lymphoma.
lymphoplasmacytic lymphoma is an infiltrated malignancy of the bone
marrow with abnormal plasma cell called lymphomoplasmacytic lymphocytes. These cells will
cause an abnormally high secretion of IgM. Also the abnormal cells, the lymphoplasmacytic cells,
will begin to invade the marrow the lymph nodes and the
spleen. As the disease progresses, this disorder has a insidious onset meaning
that it comes on slowly and is typically seen in patients in the 60s & 70s.
Typically literature in the past has used the name Waldenstrom's
macroglobulinemia, which is an eponym for this disorder, however many texts have been switching to lymphoplasmacytic lymphoma.
name and many board exams have now been following that
trend, so it is important to know both names- Waldenstrom's macroglobulinemia
and lymphoplasmacytic lymphoma because at this point not all exams have converted over to the new
accepted name. Plasma cell infiltration is one of the major clinical features of
lymphoplasmacytic lymphoma. Plasma cells will start to invade the bone
marrow and will lead to problems, such as anemia and thrombocytopenia is due to
decreased production of normal cells due to the infiltrate, you can also have
infiltration of the plasma cells into the lymph nodes causing lymphadenopathy,
as well as the spleen leading a splenomegaly. In patients with lymphomoplasmacytic
lymphoma there is also hyper viscosity which can
cause visual and hearing disturbances, mucosal bleeding, possibly CHF, and altered
consciousness. In these patients the hyperviscosity is related to the
elevation in the immunoglobulin and in the case of lymphoplasmacytic lymphoma
this is specifically immunoglobulin M or IgM. Patients also may present with
peripheral neuropathy in lymphoplasmacytic lymphoma and at this time it is
of unknown etiology. To differentiate lymphoplasmacytic
lymphoma from multiple myeloma it is important to realize that
there are no lytic bone lesions and there is not renal damage associated
with this disease.
The laboratory diagnosis of lymphoplasmacytic lymphoma will in first involve a CBC annd peripheral smear. These tests will show
an anemia and possibly a thrombocytopenia. The other thing you
will be looking for specifically on a peripheral smear is for red blood cells
to be in Rouleaux formation the word "rouleaux" refers to "cylindrical stacking
of coin," which describes the peripheral smears- red blood cells you can see here
are some nice examples of red blood cells and Rouleaux formation and this
occurs because of increases in plasma proteins. In the case of lymphoplasmacytic
lymphoma this is due to an IgM protein. You could also see Rouleaux
formation in multiple myeloma which is due to IgA. it is also possible to see
where the Rouleaux formation occur due to other increases in plasma proteins which are
commonly seen with things such as infections inflammation or connective
tissue disorders. And the the peripheral smear may also show some of the plasmacytic
lymphocytes in the peripheral blood. Abone marrow biopsy for a patient
with lymphoplasmacytic lymphoma will show inflammation of these abnormal plasmacytic
lymphocytes and remember that the radiographs for the patient are going to
be normal- there will not be lytic lesions like you see in multiple myeloma.
There is no standard treatment for lymphoplasmacytic lymphoma. Patients with
hyperviscosity issues may require emergent plasmapheresis.
There are some chemotherapeutic option for lymphoplasmacytic lymphoma
including rituximab, fludarabine, bortezomib with the most likely to be
used being rituximab which is an anti-CD20 medication which anti-CD20 will
work against B-cells- remember that a plasma cell is a type of B-cell so this
tends to be the most promising treatment for patient. Some patients will also
qualify for him hematopoietic stem cell transplant and the survival can be a
little lower for these patients with a median survival of 5 years and 10% at 15
years and this is related to some of the other complications of this disease. The
most concerning issues seen in patients with lymphoplasmacytic lymphoma is
hyperviscosity syndrome which is an increase in the serum viscosity. This is
due to increase of circulating plasma proteins and in this case it is
specifically IgM. Hyperviscosity syndrome is seen in about 10 to 30 percent of
patients with lymphoplasmacytic lymphoma. You could also see hyperviscosity
syndrome and in patients with multiple myeloma and in this case it is due to
circulating levels of immunoglobulin. The symptoms of hyperviscosity syndrome
include fatigue, headaches, blurred vision, mucosal bleeding, mental status changes,
coma, and transient paresis. Patients with hyperviscosity syndrome should be
treated with urgent plasmapheresis to bring the viscosity of their serum down.
This is considered a medical emergency and it is always important to remember to
never transfuse a patient who is hyperviscous even if they are anemic.
Thank you for listening to the Lymphoid Disorders lecture for the Hematology and
Oncology unit of the General Medicine course. Please be sure to have your study
guide completed for the Application Session for this class. Thank you!
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