Diffuse Large B Cell Lymphoma (knowing your ABC's and GCB's)

Growing up, I religiously read the comic strip, “The Far Side.”  In one strip I remember clearly, there was a woman reading her veterinary medicine textbook.  In chapter 9 she came to equine medicine where the remedy for just about anything that bothered a horse was exactly the same.  The captions said, “Like most students, Doreen breezed through equine medicine.”  I’ve posted a link here for a quick laugh.  Sometimes treating patients with diffuse large b cell lymphoma (DLBCL) can feel the same  - R-CHOP for all (here is a description of R-CHOP and my personal approach to DLBCL).  

If you look at the most recent update of the world health organization classification of blood cancers, they identify thirteen different types of “aggressive lymphoma.”  Most patients are familiar with the most common subtype lovingly called DLBCL-NOS (not otherwise specified).  The “plain vanilla” DLBCL proves to be far and away the most common version of the disease.

Despite being lumped together as a single entity, if you pop the hood and look deeper inside DLBCL-NOS, there is a lot of biologic heterogeneity – those differences are starting to look more and more important.  A number of years ago, one of my colleagues (who I still insist is the smartest guy I’ve ever met – Ash Alizadeh at Stanford) took advantage of a brand new technology called “Gene Expression Profiling” to look at a bunch of DLBCL samples and got his findings published in the journal Nature.  Other labs (Lou Staudt at NIH and Margaret Shipp at Dana Farber) had similar findings – it is pretty robust.  This allowed scientists to take cancer samples and test them to see which genes were turned on and turned off (a term we call “expression”) and evaluate tens of thousands of genes at a time.

What they all found was that there were two “main” subtypes of DLBCL-NOS.  Those two subtypes were the “Germinal Center DLBCL” and the “Activated B Cell DLBCL” (GCB and ABC subtypes respectively).  Purists who know the science well could fault me for not being completely precise here, but that will do for now.  When normal B cells undergo proliferation in response to discovering the “germ” they were destined for all their life, they do so in a specialized region of the lymph node called the “germinal center.”  GCB-DLBCL-NOS appears to have similar genes turned on and turned off (ie expressed) whereas ABC-DLBCL-NOS looks like a cell that has left the germinal center in an “activated” state.”

Why does this matter?  It turns out that these biologic differences have significant clinical impact.  If you segregate ABC from GCB DLBCL, the ABC do quite a bit worse than the GCB in terms of overall survival and response to R-CHOP chemotherapy. 

Since there is such a big clinical impact, you would think we would all know if our DLBCL patients were ABC or GCB subtype – but we don’t!  It turns out that gene expression profiling (GEP) is pretty expensive and it has to be done on biopsies handled a certain way that most surgeons / pathologists don’t do.  Instead of GEP testing, pathologists figured out how to make the determination of ABC vs. GCB using tests that are a lot cheaper and easier to use – called “immuno-histo-chemistry” (or IHC).  Any pathologist who looks at cancer specimens knows how to do IHC.  You essentially take a small slice of the tumor / lymph node / marrow / etc., stain it with an antibody of interest, and use a marker on the antibody to help you know if it stuck after you washed the heck out of it.  ABC has different IHC staining than GCB DLBCL when you look at markers like CD10, BCL-6, MUM-1, and so forth – so just about any lab can do this testing – but they don’t always do it!  There are two main reasons why many don’t.  First, the test isn’t nearly as reliable as GEP testing.  In fact, there are several different antibody combinations that can help make the IHC distinction, but get a bunch of pathologists together and they will only agree about 70% of the time when they do the stains themselves.  The second reason is when I come back to the far side comic strip.  At least for now, you pretty much have the same R-CHOP no matter what the test shows – but that is starting to change.

For patients interested in a purely “prognostic” test, I suggest getting this one done.  It distills all of the gene expression profiling down to two genes and can be ordered easily today.

Since fewer than half of ABC DLBCL patients are likely to be cured with their R-CHOP chemotherapy, lots of pharmaceutical companies are interested in building a better version of R-CHOP.  Quite a few drugs have been explored in DLBCL in the last few years that seem to have preferential benefit in the ABC subtype of DLBCL.  Ibrutinib yields a 40% response rate as a single agent in relapsed ABC-DLBCL but only a 5% response rate in GCB subtype.  For Celgene’s lenalidomide, it is more like 50% versus 5%.  Millennium’s bortezomib can be added to R-CHOP and when you look at the patients with ABC vs GCB, they do almost identically suggesting that the drug overcomes the negative impact of the ABC subtype of the disease.  Indeed, adding ibrutinib to R-CHOP gives a 100% response rate in preliminary studies, and adding lenalidomide to R-CHOP makes the ABC look ever so slightly better than the GCB subtype.  Not surprisingly there is intense interest in ongoing phase III studies that restrict enrollment to patients with ABC subtype DLBCL to see if any of these three drugs can be added to standard R-CHOP.

My prediction?  I bet several of these end up crossing the finish line and getting approved by the FDA (disclaimer: I am not currently involved in ANY of these studies and have not seen any preliminary data).  So what happens if two or three such drugs actually get approved – how would a doc and patient choose which combo to take?  Now we go back deeper into the biology.

If we look at gene expression profiling or use immunohistochemistry staining to categorize DLBCL-NOS into ABC or GCB we are really only using surrogates for a more fundamental process – what mutations have occurred at the DNA level.  Several publications have recently come out where the entire genome of DLBCL has been “sequenced” and when you look at the data, you realize there are a handful of mutations that seem to recur.  Those mutations often determine which genes are expressed, and how the cell looks under the microscope when you use IHC.  In essence GEP and IHC are merely proxies for the underlying mutations.

Here is where it gets really interesting and makes a lot of sense.  The ABC subtype of DLBCL appears to have “chronic active signaling” through the B-Cell receptor (BCR).  This has some similarities to what we have seen in CLL through different mechanisms.  If you look at the BCR signaling pathway (think of an electrical circuit), you can create a “short circuit” at any number of steps along the way, yet the result seems to be a light that either won’t turn on or off appropriately.  In this case, that is a protein called NF-kB which regulates the expression of a bunch of important B cell genes.

If that short circuit is really high up in the pathway (CD79 stuck in the “on” position) or low in the pathway (CARD-11 mutation) you get the same activation of NF-kB, but turning it off at different places may make a difference.  BTK is a protein that lies just “downstream” of CD79 in the BCR signaling pathway and lies “upstream” of CARD-11.  It is also the target for ibrutinib.  You can have ABC-DLBCL where there is a mutation in EITHER CD79 or CARD11.  Interestingly, very preliminary work makes it look like ibrutinib works well when there is a CD79 mutation but it isn't clear yet how well it works when  there is a CARD-11 mutation.  This makes a lot of sense.  To get to NF-kB, BCR signaling from abnormal CD79 has to go through BTK but BCR signaling that starts from abnormal CARD-11 does not.  That would perfectly explain why ibrutinib might work in one case but not the other (if larger numbers of patients make that theory hold up).

A similar but different story may be developing for lenalidomide where either MYD88 mutations or others may explain when that drug works or doesn’t.

So my challenge to my pharma colleagues is the following: figure out which mutations confer activity for your drug (as some are trying to do right now) so that the docs know what to do once your drug is approved.  Molecular diagnostic tests are now available that enable you to test for each of these mutations all at once.  This should be in their interest anyway because the FDA loves "companion diagnostics" for selecting individuals for therapy.  I predict that in the future, DLBCL management will go like this:

Patient walks in with new diagnosis of DLBCL

Since therapy is often needed very quickly, the patient will get their first cycle of R-CHOP

While the three weeks between cycles has passes, the patient will have their cancer sent for analysis and they will find out what unique mutations they have

The patient will come back for the second dose of therapy and an appropriate targeted drug will be added based upon the mutation analysis

In some cases no “pathway specific” mutation will be found.  In these cases, there are other drugs working through the system that may be added like the antibody drug conjugates (see here and here).  Pharma companies developing such drugs would be wise to know where their drug works even if it is felt not to be mutation specific so that they can pick up the pieces for the patients who don’t get ibrutinib, lenalidomide, bortezomib or others.

R-CHOP has served us well for quite a few years.  We are spoiled in NHL management that we get to cure a lot of our patients.  It is really fun as a doc to have a patient walk in doing great with their cancer a fading memory.  Unfortunately “a lot”doesn’t feel that great if you are not one of the ones who is cured.  I think we are getting really close to making some important steps forward in the management of DLBCL-NOS and it will be driven by molecular information that leads to targeted therapies that are specific to the patient.

Thanks for reading!

Jeff

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. 

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....