If you took blood samples from individuals on an annual basis and stuck them in the freezer for analysis sometime later, you would find that virtually everyone diagnosed with CLL once had monoclonal B cell lymphocytisis (MBL). On the other hand if you took everyone with MBL and followed them for many years, you would find that only a small number of them would develop CLL. A smaller number would even develop NHL.
As a hematologist, I am commonly asked to see patients who have slightly abnormal blood counts. Occasionally these patients have a lymphocyte count that has been outside of the normal range on several occasions when the primary care doc decides to send them my way.
In the absence of an obvious viral infection or other acute illness, I will order a test called "flow cytometry." Flow is a complicated test that is able to look at different surface markers on the outside of cells. We use the term "CD" a lot and it stands for cluster of differentiation. As these different markers were discovered they were given different numbers - there are now several hundred (CD5, CD19 and so forth). I posted a video explaining it all because it can get very confusing. The test can tell you a lot about why lymphocytes are out of whack.
A common explanation is "Monoclonal B Cell Lymphocytosis" (MBL). Unfortunately, the subtle nuances of MBL are lost on many docs - or perhaps they just don't take the time to fully explain it to a patient. One way or another, quite a few patients can be given quite a scare - do I have cancer or not?
MBL is a descriptive term worth explaining. "Monoclonal" means that there is a single population of cells (a clone) that look identical. In the normal healthy situation B cells should look different from one another. When they all look alike, we get worried that it could be a sign of cancerous growth. "B-Cell lymphocytosis" means that the ratio of lymphocytes are off and there are too many of them. Normally 85-95% of the lymphocytes in the blood should be "T cells," 5-10% should be "B cells," and the remainder are called NK cells.
In normal physiology, individuals may have a white blood cell count of 4-11 thousand with 20-40% being lymphocytes. So at the upper range there may be about 4000 lymphocytes and about 10% (around 400 cells) should be B cells. These are ballpark estimates and can be fairly variable.
In MBL an individual may have up to 5000 monoclonal B lymphocytes per microliter. They should also not have enlarged lymph nodes, a big spleen, or other symptoms of lymphoma / CLL. If the numbers are higher or the nodes / spleen are enlarged there is something more going on.
It is important to note that we use 5000 B cells as an arbitrary cutoff. While it is true that the higher the count, the more likely the patient is to develop CLL, we always try to make categories of patients even if it is really just a continuous variable. I don't think that a patient with 4999 monoclonal B cells is really all that different than somebody with 5001 but we label one MBL and the other CLL.
If we stop there it would worth noting that anywhere between 4-8% of the entire population of individuals over the age 60 will have MBL. Only a small fraction of them will ever develop CLL. In a very imperfect analogy, I might compare it to a colon polyp detected at colonoscopy. It is not cancer, but it could become cancerous at some point.
We break MBL apart into different categories based upon how it was detected, and how it looks on flow cytometry.
"Clinical MBL" is identified when flow cytometry has been ordered on the basis of an elevated lymphocyte count on the CBC. "low count MBL" generally has much lower number of monoclonal b cells (typically less than 500) and is identified by population screening. Obviously the risk of becoming CLL or something else is much higher in clinical MBL. That risk is about 2-3%/year. In lcMBL there is very limited risk of developing CLL.
When we look more closely at the specifics of flow cytometry - there are actually several different types of MBL. Typical MBL looks exactly like CLL. It has bright CD5, 19, 23, and dim CD20 (see flow cytometry). It accounts for about 85% of all MBL. Atypical MBL has bright CD5 but lacks CD23. The CD20 may also be brighter. Finally, a third category of MBL is the "non-cll phenotype" in which the CD5 is negative. Atypical MBL may in fact be a precursor to mantle cell lymphoma rather than CLL. "Non-cll phenotype" MBL may represent blood involvement of NHL. Several of the indolent NHL's can have involvement in the blood and I have seen them confused for CLL by other docs quite a few times. Many general oncologists are unaware of these differences.
Classic MBL may just be a manifestation of small lymphocytic leukemia (SLL) that has a little bit in the blood. If I feel enlarged lymph nodes, that is high on my list. In patients with either atypical MBL or non-CLL phenotype MBL, I am a little more quick to order a CT scan of the chest, abdomen, and pelvis to make sure I am not missing a lymphoma that has spilled out into the blood (it is not uncommon to have lymphoma in the blood). I don't think the guidelines dictate that everyone with either atypical or non-cll MBL require a CT scan, but I might be more inclined to order one if the history suggested it.
In CLL we often test for IgVH (BCR) mutation analysis, and FISH. In MBL, the same genetic changes can be seen but since the number of B cells is so much lower, the tests don't work quite as well. In reality, it is very easy to purify the B cells to the degree necessary to run the tests, but since it is only a minority of patients who go on to develop CLL it is reasonable to wait until they have a higher count before running those tests.
So how closely do these patients need to be followed?
It sort of depends on how worried I am that they are actually going to develop CLL. I might like to see someone back in 3-6 months just to make sure things haven't changed much. If they are on the low end, I could certainly go farther out. If things hadn't changed much, seeing them once a year is reasonable. If I think the patient has a good primary care physician, it is reasonable to think that the PCP could even follow the patient and send them back to me if they felt the counts changed much.
Keep in mind that we do not routinely repeat the flow cytometry to check when the "monoclonal B cells" rise above 5K. Instead, we just look for a rising trend in the lymphocyte count. When the lymphocyte count is more consistently elevated we just start to call it CLL. If lymph nodes and spleen have not enlarged, it is still "stage 0" CLL. All the arguments for "watch and wait" and when to treat still hold true. Patients with stage 0 disease often still have an excellent prognosis.
There are not really a whole lot of "guideline papers" out there for MBL. I came across this review and I might suggest it for the interested reader. Published Review for MBL.
Thanks for reading
Jeff
