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?
Clinical studies have tried to get at differences in outcomefor patients with grade IIIb follicular lymphoma but drawn somewhat different conclusions. (another link here and here)
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!