Tuesday, April 16, 2013

Follicular Lymphoma Grade and Stage

A while back, one of my readers asked if I would make a post about “grading” in follicular lymphoma.  She has been a great help to me in attracting readers to this blog so I promised her I would write something up.  Unfortunately I think I’ve had a mental cramp on this one for a while – but I am trapped on a seemingly endless flight (Dang Texas is big) so I thought I would give it a try.  The flight doesn’t have internet so this one may be a little brief on the outside references.
Most of you know about “staging.”  In lymphoma, staging is a clinical measurement of how much disease you actually have.  Stage I disease is typically one affected lymph node or a few that are tightly clustered in one place.  Stage II disease is when there are multiple affected lymph nodes in different areas, yet on the same side of the diaphragm (ie all in abdomen/pelvis or all in neck, chest, armpits).  In stage III disease you can have lymph nodes on both sides of the diaphragm.  Stage IV disease is when it either involves the marrow or more than one site outside of the lymph nodes (ie skin, liver, lungs, bone lesions).
I should make a comment here that frequently comes up in my clinic.  Patients often ask me, “what stage am I?”  There is nothing worse than the look you get when you tell someone they have stage IV disease.  We are primed from our knowledge of a lot of cancers that stage IV means you are going to die.  It can sometimes be a challenge to “pick up the pieces” after you tell someone their disease is that far advanced.
Stage IV lymphoma is very different than stage IV lung cancer.  I tell my patients that lymphoma is a cancer of the immune system and that the immune system is pretty much everywhere to begin with (ok – we can make exceptions for both the brain and testicles which are considered immune “privileged”  - draw your own conclusions).
In diseases like lung cancer, if that cancer has spread outside of the lung or adjacent lymph nodes – that becomes an incurable disease and the prognosis is often comparatively short.  Same thing holds true with a bunch of other “solid” tumors for that matter (bladder, kidney, pancreas, colon, stomach, and so forth).  It is certainly true that less lymphoma is better than more lymphoma – but not to the same degree as those other cancers.  Stage IV lymphoma is very common but often still quite manageable (and even curable in DLBCL).   In fact stage III/IV follicular is considerably more common than limited stages of disease – so most of the statistics you hear about survival  are typically for patients with advanced stage disease (which are often way outdated since by their very definition are retrospective and do not necessarily account for improvements in therapy).
OK – moving on – this was supposed to be about grading right?  Grade has absolutely NOTHING to do with stage.  I tell patients, “grade is what it looks like under the microscope – stage is what it looks like on the CT scan.”  Unfortunately, there is a fundamental problem with using appearance under a microscope as an objectivemeasurement – it is difficult to reproduce this well.  Even though there are well established criteria about grading lymphoma – trying to make solid black / white distinctions can be hard when the biology does not conform to the rules.  You can look at different regions of the same node and come to a different answer, or you can even look at the same region and have two different pathologists give you a different answer if they count things a little differently – and that is easy to do!
Grading typically applies to cases of follicular lymphoma.  We assign one of four grades – you would probably guess I, II, IIIa and IIIb right?  The way we distinguish between these are the number and arrangement of “large cells” within a node.  Large cells are typically called “centroblasts” while small cells are called “centrocytes.”  Large cells are thought to be more rapidly proliferating.  Since faster proliferation is bad, the more large cells you have the worse we think it would be.
Ultimately, there is VERY LITTLE difference between the grade I’s and the grade II’s either biologically or clinically.  Even grade IIIa disease is pretty much something we can lump together.  We treat them exactly the same way, they do just as well.  It is pretty much just a pathology distinction without much clinical impact.

Distinguishing between grade IIIa and IIIb though can have clinical implications.  In grade IIIa there are enough centroblasts seen in the lymph node (15  per “high powered field”) to be categorized differently than grade II yet clinically we still treat all these exactly the same.  Grade IIIb on the other hand has “sheets” of centroblasts within the node and really starts to behave more like diffuse large B cell lymphoma (DLBCL).  In the past that often meant the difference between getting R-CVP or R-CHOP (the latter being more intensive and causing hair loss – see my post about it). For a lot of docs though, R-CHOP was historically (and still is in some cases) the choice though even in grade I-IIIa  follicular lymphoma so the distinction didn’t matter quite so much. 
Now it is more significant because in grade I-IIIa utilization of bendamustine-rituxan is extremely common yet R-CHOP would probably still be considered standard for IIIb.  Since BR is both superior and better tolerated than R-CHOP in I-IIIa, I sometimes anguish a little when I see a IIIb come into clinic. I will often call the pathologist to get a better feel as to how “clear” the distinction is to them in the sample.  Alternatively, I may look for other clues about the aggressiveness of the disease.  Does a PET scan show one area to be a lot worse than others to suggest a transformation?  Does the clinical pace or labs suggest higher grade disease? etc.?
There are a few problems with this though.  1) This is an area where pathologist reproducibility is not so great.  This is not to say they are not good pathologists but that there is a lot of judgment involved as well as sampling differences.  2)  It is not clear that appearance is a good surrogate for biology.  We are learning about the remarkable complexity of these cancers and I am not convinced that appearance gives us adequate insight into the molecular mechanisms that are going on.  3) As humans we like to compartmentalize things even if they are really continuous variables.  In other words, if we use the number 50 as a cutoff – are patients with 49 or 51 really all that different from one another?
If good researchers come to different conclusions when asking some of the same questions – it is often because the data input is faulty (ie. in a study of 100 patients- 15 are categorized incorrectly and results in a smaller difference than would have occurred if everyone was put in proper group).  Other times we may be falling victim to the belief that appearance is a surrogate for biology AND that the biology is actually different.
One other key point I should make before wrapping up.  Grade IIIb is not the same thing as histologic transformation which is evolution from low grade disease to high grade disease.  We are getting to understand that biology better and histologic transformation is likely worse than grade IIIb on account of a different mutation profile.
For now, grades I-IIIa can be treated with rituxan, R-CVP, R-CHOP, BR, or any of the new research drugs.  See my posts on “my approach to follicular lymphoma part 1 and part2.”  Grade IIIb I will use R-CHOP even though I have all the questions I ask above.

I hope that helps – thanks Anjou!