Monday, December 31, 2012

The Slow (Indolent) Lymphomas

In my prior post "Understanding The Different Types of Lymphoma" I spent a bit of time explaining how there were three main categories of B cell NHL; slow, medium, fast.  I encourage readers of this post to review the prior post if coming to this for the first time.

The slow lymphomas probably have the greatest number patients falling into different disease categories.  I've had a lot of traffic on my website for the intro post so I thought it was time to go deeper into detail for some of the "indolent - aka: slow" lymphomas.

For now, I am going to restrict the discussion to the B cell cancers.  Many of the T cell disorders that affect the skin are also considered "indolent" but they are really an entirely different discussion probably best saved for later.

Follicular lymphoma 
(read this even if it isn't the type you have)

The most common indolent lymphoma is follicular lymphoma.  In fact, this is the second most common type of NHL.  In a number of important ways, you can generalize from follicular lymphoma to many of the other indolent subtypes of lymphoma.  I've got a few blog posts that outline what I think is the current approach I use to treat the  disease (low risk & high risk).

Follicular lymphoma comes in many shapes and sizes - there is considerable diversity in terms of patient presentation.  It can range from an asymptomatic enlarged lymph node that does not require any treatment - all the way to life threatening cause of marrow or organ dysfunction.  I have a number of patients in my clinic who have carried the diagnosis for many years never requiring any therapy.  In fact, I have one patient originally diagnosed in the 1950's still chugging away - pretty remarkable.

Pathologists determine the diagnosis of follicular lymphoma in several ways.  In fact, if you simply hold a microscope slide of a lymph node up to the light, you can often have a pretty good idea that you are dealing with follicular lymphoma.  They look for a particular growth pattern (nodular), cell size (mostly small), and can use a handful of special stains (CD10, 19, 20 positive, CD5, 23 negative) or DNA probes (translocation of chromosomes 14:18) to verify the diagnosis.

The name "follicular" comes from the "cell of origin."  When a b cell runs into the bacteria or virus it was born to fight it goes into the "follicle" of the lymph node.  There it undergoes a number of changes to make it a better infection fighter and spits out a bunch of copies of itself.  It is a genomically unstable time in the life of a b cell (see my post: why did I get lymphoma) and can give rise to a lymphoma.  When lymphoma starts here it is typically either a follicular lymphoma or a diffuse large b cell lymphoma.

When I consider a new patient with follicular lymphoma, there are several key features I want to know about before making my management decisions:  1)  What stage is the patient?  2) How much disease do they have? 3) How aggressive does it look?  Though you might think these three characteristics are all the same, I actually think they are quite different.

Stage is fairly straight forward in NHL terms but often misunderstood by a patient who is already shellshocked by the diagnosis.  It is quite common for follicular lymphoma to be stage 4 at diagnosis but that is very different than a lung cancer that is stage 4.  Since lymphoma is a cancer of the immune system, it is pretty much everywhere to begin with.  In contrast, a lung cancer that has spread beyond the confines of the lung and lymph nodes has "metastasized."  We don't think of lymphoma as undergoing "metastasis."  While stage 4 follicular lymphoma is typically worse than stage 2 follicular lymphoma, I would still take it over stage 4 lung cancer any day.  Stage 1 is a single lymph node, stage 2 is lymph nodes confined to one side of the diaphragm, stage 3 is  lymph nodes on both sides of the diaphragm and stage 4 involves the marrow.

Embedded within "stage" though is a consideration of how much disease a patient has.  If a patient has an 18cm lymph node in their abdomen and nothing in their marrow - I still worry more about that patient than the one with a handful of 2-3 cm nodes in the chest and abdomen and a little bit in the marrow.  We refer to this as tumor "bulk."  It is often a subjective evaluation but one that is important.  If there is a single disproportionately large node we begin to worry about transformation.  Sometimes a PET scan or additional biopsy is necessary.

Aggressiveness is another qualitative / semi-quantitative evaluation.  Pathologists will assign a "grade" to the lymphoma that is either 1, 2, 3a, or 3b.  This is a measure of how many "large cells" are visible.  Large cells are bad as they tend to be more proliferative.  The lower the grade the better.  Unfortunately there is a lot of variability between pathologists when they try to sort out the 3a/3b's.  We are taught to think of the 3b's as the same thing as diffuse large B cell lymphoma.  Pathologists can also use a marker known as Ki-67 that indicates how many cells are in the cell division process.  Once again, the lower the better.

There is a score that does a pretty good job integrating a lot of this known as the FLIPI score.  It looks at patient age, stage, number of nodal sites, marrow function (hemoglobin), and a blood test known as LDH.  The higher the worse.  FLIPI is helpful for allowing us to evaluate results across trials and getting a sense of an individual patient but I still take the other measures as important as well.

Anyhow, that is the basics of follicular lymphoma.  See my other posts for treatment etc.

Marginal Zone Lymphoma

Marginal zone lymphoma is a lot like follicular lymphoma in terms of how it shows up, behaves clinically, gets treated, etc.  There are a few key differences though that are worth pointing out.

The first difference is seen by the pathologist.  It arises from a different part of the lymph node architecture (any guesses - yes - the marginal zone - which surrounds the normal follicle areas).  They often do the same panel of stains on the sample but in contrast to follicular lymphoma, it is negative for CD5, 10, 23, and positive for CD19, 20.  They don't necessarily look for the translocations common to other lymphomas like 14;18 in follicular or 11;14 in mantle cell - largely because they are not there.

Marginal zone lymphoma comes in three main varieties, nodal, primary splenic, and extranodal mucosal associated lymphoid tissue (Aka MALT).  The nodal variety may as well be follicular lymphoma in terms of treatment, prognosis, etc.  Some of these can make really highlight how slow these lymphomas can be.

Primary splenic marginal zone lymphoma is a little interesting.  It can be closely related to hepatitis C.  In fact, treating hepatitis C in these patients can even lead to remissions of the lymphoma.  Hep C probably gives some growth signals to B cells - so if you get rid of the hep C the lymphoma can go away.  It is certainly worth an attempt at Hep C treatment and it should be noted that Hep C treatment is getting a lot more effective.  This disease is often also often confused with CLL to a doc unfamiliar with lymphoid cancers.  Sometimes you see an elevated lymphocyte count in the peripheral blood, the flow cytometry shows a b-cell cancer, and the doc misunderstands this to be CLL.  In the past this might not have been too big of a deal but now that there are some extremely effective CLL drugs, getting the diagnosis right might be more important.

Finally the extra-nodal varieties that are associated with mucosal tissues (the lining of the stomach, tear glands, etc) can be interesting because of their associations with paticular infections.  The stomach version can be associated with the same H. Pylori bacteria that causes ulcers.  Treating the bacteria is often effective at getting rid of the lymphoma.  The eye version can be associated with a chlamydia infection (no not the sexual transmitted disease).  Here too, treating the infection can cause remission of the lymphoma.

Small Lymphocytic Lymphoma

Small lymphocytic lymphoma (SLL) is essentially chronic lymphocytic leukemia (CLL) except it affects the nodes more than the blood and marrow.  The two disases are so similar we often refer to them together as CLL/SLL.  We arbitrarily define CLL as cases with lymphocyte count greater than 5000.  In virtually all other ways the two disease are the same.

The pathologist will often look at a node and call it SLL/CLL when it stains positive for CD5, CD23, and CD19.  The B cell receptor is characteristicly "dim" so any BCR markers such as kappa, or lambda or CD20 are present at lower levels than other B cell cancers.  Translocations are not common.  Unfortunately the same FISH tests that are so vital in CLL are often not obtained in SLL.

Staging can sometimes seem "unfair" to the patient because of how arbitrarily the distinction between the two diseases (CLL vs SLL) are defined.  In SLL, staging is done in the same way as follicular lymphoma above.  In CLL staging is different though.  Stage 0 is elevated WBC, Stage 1 has WBC and enlarged nodes, Stage 2 has the above and an enlarged spleen, Stage 3 has low red blood cells and stage 4 has low platelets.  Therefore a SLL patient who has a few nodes and some marrow involvement but a lymphocyte count of 4900 is stage 4 SLL, but if they had a count of 5100, their CLL would be stage 1.  It is arbitrary and unfair because they are really the same biologically and calling it stage 1 or 4 sounds a lot worse than it really is.

The other thing about SLL that is important and sometimes overlooked is that it should be approached in the way one things about CLL instead of follicular lymphoma.  A lot of docs will give lymphoma regimens for SLL when it probably makes more sense to use CLL regimens.  I would tend to favor fludarabine based treatment instead of things like R-CVP.  It is also important because the new drugs like CAL-101 and ibrutinib are quite active in SLL and should be considered.

Mantle Cell lymphoma

It isn't totally clear if mantle cell lymphoma belongs in a discussion of the "slow lymphomas."  Mantle cell can take on the "incurable" clinical features of follicular lymphoma while sometimes having the growth rates of the more aggressive diffuse large B cell lymphoma.  It gets the worst of both.

Our knowledge of Mantle cell lymphoma is clouded by the fact that we didn't even recognize this as a discrete type of lymphoma until the mid to late 1990's.  Some of the early reports may have been biased by more aggressive cases.  More recently, we've come to identify that some mantle cell really can indeed behave slowly.

The lymphoma gets started from yet another part of the lymph node - the mantle zone.  It stains positive for CD5 but negative for CD23 in distinction to CLL/SLL.  Mantle cell does have a characteristic translocation between 11:14 resulting in too much "cyclin D-1"  Sometimes this test helps a pathologist determine whether it is CLL or mantle cell.  In B cell biology mantle cells arise from B-1 b cells which are similar to CLL.  It is therefore interesting to me that the research drugs ibrutinib and ABT-199 look very exciting in this disease since they are also so impressive in CLL. 

Mantle cell has another few curiosities.  It loves the colon.  In order to fully stage a patient, it is sometimes necessary to do a colonoscopy and get "blind biopsies."  GI docs are often unaware of this so sometimes it requires some physician education.  Not every patient needs a colonoscpy but it is common in clinical trials or chasing down symptoms.

Treatment of mantle cell lymphoma is all over the map.  It can range from transplant to observation.  I should probably just save that for another post.  Instead of using the FLIPI from follicular lymphoma, we use the MIPI (mantle cell international prognostic index).  It uses age, functional status, WBC count, and LDH.  The original paper did not use the proliferation rate called the Ki-67 but this is very important (<10%, 10-30%, >30%) and separates prognosis quite well.

Waldenstrom's (lymphoplasmacytic lymphoma).

Waldenstrom's is named after the Sweedish hematologist who characterized the disorder.  It is often a marrow only disease that arises from a b-cell en-route to becoming a plasma cell (the type of B cell that gives rise to multiple myeloma).  It can involve lymph nodes however so that should not give rise to diagnostic confusion.

One unique feature to this disease is that it secretes an antibody into the circulation that can cause a variety of problems.  The particular form of the antibody (IgM) is a big / bulky molecule.  If the concentration gets too high it can make the blood become too viscous (think olive oil in the refrigerator).  In fact "hyper-viscocity syndrome" can be a life threatening situation that requires emergent "plasmapheresis" which is a lot like dialysis.

One odd consequence of using rituxan in this disease is that it sometimes leads to a sudden rise in the antibody levels.  To the unsuspecting doc, this can be confused for progression.  If patients start with a high level of protein, this spike can be dangerous and should be monitored.

The protein can cause other problems as well.  Neuropathy is not uncommon and sometimes pushes a patient toward therapy they might have otherwise been able to hold off on.

Steve Treon M.D. is the guru of this disease and practices in Boston.  In addition to being extremely helpful to patients and other docs managing these patients, he has done a fantastic job organizing a number of academic centers into a combined research effort.  Since the disease is uncommon, it would never get much research attention if it were not for the combined effort of some of the major centers.