Friday, August 24, 2012

Making sense of all the different lymphomas

I am not sure if there is a single person on the planet who can tell me exactly how many different types of lymphoma exist.  I live and breath lymphoma and I can't.  Perhaps Elaine Jaffe M.D. could since she is the pathologist in charge of the world health organization committee responsible for lymphoma nomenclature, but I would wager that she might pause before giving you an answer.  I think the number is somewhere between 70-100 different types - but it sort of depends how far into the weeds you want to get with your counting.

Take the most common form of NHL known as Diffuse Large B Cell Lymphoma (aka DLBCL) and you could have such variants as primary CNS (brain) DLBCL, primary mediastinal (between the lungs) DLBCL, intravascular DLBCL, gastric (stomach) DLBCL, activated B cell DLBCL, germinal center DLBCL, DLBCL of leg, etc. Remarkably each of these entities has a fairly significantly different biology / prognosis and they warrant unique classification.  It is not merely the part of the body where they show up, they are actually different diseases.

If you even venture to take a single entity like "activated B-cell DLBCL" there may be key molecular differences that could split this disease into multiple subtypes depending on whether there is a CD79b mutation versus a CARD11 mutation or a MYD88 mutation which could be the key difference in responses to drugs like ibrutinib.

This bewildering complexity is one of the reasons I most enjoy being involved in lymphoma / CLL.  Even amongst seasoned oncologists, you can often look like the brightest person in the room when you talk about subtle patient management differences in uncommon variants.

Unfortunately this bewildering complexity can also be overwhelming for a patient who is told by their surgeon that they have lymphoma and need to see an oncologist.  The delay between the diagnosis and the consult is often filled with an internet search that feels like a trip through Alice in Wonderland.

When I meet a patient with lymphoma I always explain how these different diseases fall into a few limited categories and how those categories are unique.  Hopefully you will find this useful.

The first "branch point" is the difference between Hodgkin's Lymphoma and Non-Hodgkin's Lymphoma.  Patients always ask, "Which is better?"  Of course there are a lot of variables that determine the answer to that so I usually say, "stick with me for a minute... we will get there."

Among the patients with Non-Hodgkin's Lymphoma (which outnumber Hodgkin's by about 5:1), my next branch point is T cell versus B cell.  In normal physiology, B cells are responsible for making antibodies and T cells are either the "brains" of the immune system or the "cellular assassins" that go around looking for a rogue cell to annihilate.  B cell lymphoma outnumbers T cell by about 9:1 so when most people talk about lymphoma they are talking about one of the subtypes of B cell Non-Hodgkin's Lymphoma.

So if we focus for now on the different types of B cell Non Hodgkin's Lymphoma the next branch point splits into three categories based more on clinical behavior.  I call them "slow, medium, and fast." In official parlance they are "indolent, aggressive, highly aggressive."  Within each category, there is one form of NHL that is the most common and it becomes the "prototype" of the category - for better or for worse.  Slow = Follicular Lymphoma (all my FL posts can be linked here), Medium = Diffuse Large B Cell Lymphoma, Fast = Burkitt's.  There are a bunch of other slow lymphomas such as Marginal Zone Lymphoma,  MALT lymphoma, Small Lymphocytic Lymphoma, etc.  There can be considerable differences in management between these, but there is still value in lumping them together as a category.  For example, if you learn the basic features of follicular lymphoma (slow prototype), you have a good place to start then you can learn how your specific disease is different or unique.

It is important to recognize however that even a singular entity like Follicular Lymphoma can range from a disease that never needs treatment to a disease that is immediately life threatening.  There are other diseases like Mantle Cell Lymphoma that don't fit nicely into a singular category and can take on properties of both "slow" or "medium" lymphomas.

Back in medical school, they always taught us how important a patients history is.  In oncology I find this to be most true when I evaluate a new patient with lymphoma.  If that lymph node sprung up in 6 days, that is very different than a lymph node that sprung up in 6 months, or even the occasional patient who comes in and says that the lymph node has been there for 6 years.  Yes there are categories, but you cannot take a variable that has a continuous distribution and neatly put it into discrete categories!

With all those limitations, I still want to make an effort to say how the categories are different.

If you go from slow to medium to fast I tell patients that the "curability" increases and the "managability" decreases.  You are probably not going to cure a slow lymphoma, but for quite a few patients you can manage it for many years.  In the Rummel presentation at ASCO 2012, the median (half of patients do better, half do worse) progression free survival after bendamustine / rituxan was almost 7 years - even without rituxan maintenance.  That doesn't even take into account survival based on second line regimens and beyond.  Slow lymphoma is often very manageable.  I have quite a few patients out many years who have NEVER REQUIRED ANY TREATMENT!  This is the group where you often hear "watch and wait."  I understand that patients want to be "cured."  Sadly, with our current treatment regimens I don't think patients with slow lymphoma often get there (ok ignore the minority of limited stage slow lymphoma that gets radiated doesn't have their disease come back elsewhere).  I often use the analogy of having a "quiver of arrows."  You use the arrows as you need them and count on research to add arrows to your quiver as you go.  With survival that is often over a decade, that does not feel to me like a false hope.

If you go the other direction from fast to medium to slow, "managibility" increases.  On the highly aggressive end of the spectrum are Burkitt's lymphoma or Lymphoblastic Lymphoma.  Here you are aiming for cure but if you don't get there you are in trouble because it is unlikely to be very manageable.  Often you don't meet a patient with Burkitt's in the clinic.  They often get hospitalized because something has gone terribly wrong and they are hospitalized before the diagnosis is made.  Other times, you get a call from a primary care physician who has made the diagnosis and is requesting a consult.  I tell them to send the patient straight to the hospital, I will meet them there!  From the outset, you are fighting a high stakes battle.  With these diseases you often have one chance to get it right.  If things go wrong, your chance for cure gets a lot more difficult.

DLBCL is somewhere in between.  It is the most common form of NHL (about half of all cases).  The disease is quick, but often you have enough time to dot all your "i's" and cross all your "t's" before launching into chemotherapy which probably cures a little more than half of all patients.  "Watch and Wait" does not apply to this group, but you often have time to get your PET scan, bone marrow biopsy, echocardiogram, etc. as an outpatient.  For those patients not cured, it can often be in remission for years.  Even if it comes back, you often have a back-up plan that can cure them the second time around (albeit with a "auto stem cell transplant").  Not surprisingly though there is a broad range of behavior among cases of DLBCL.  In some cases it acts like a bad case of Follicular and at other times it can give Burkitt's a run for the money.

I've largely ignored T cell NHL to this point.  Though there are "highly aggressive" T cell lymphomas they are fairly rare.  Most of the systemic T cell disease fall into the same "intermediate / medium" category as DLBCL.  There are a variety of skin T cell lymphomas that are in the "slow" category.  Start talking T cell lymphoma variants and you often get a glazed look from oncologists who don't think about NHL all that often.

To summarize: we often lump NHL into one of three categories.  Though there can be a significant range within an individual category, our clinical approach to each category is unique and the expectations of patient outcome varies by category.  The prototypes (most common per category) are follicular (30%), DLBCL (40-50%), Burkitt's (5%).  The remainder of cases make up the bewildering complexity of NHL and explain why my job will likely never be outsourced....