When I was practising oncology about 20 years ago lymphomas were divided according what was known as the working formulation. The pathologists had already divided up the lymphomas into more than 20 different types, but to oncologists this was nonsense. They recognized only three types: high grade lymphoma - which was mostly acute lymphoblastic lymphoma and Burkitt's lymphoma, intermediate grade lymphoma - which was mainly what we now call diffuse large cells B-cell lymphoma, and low grade lymphoma - which was mostly follicular lymphoma. There were three treatments: vincristine and prednisone plus head radiotherapy followed by 6-MP and methotrexate maintenance for the high grades, CHOP for the intermediate grades and CVP for the low grades.
We've come a long way since then and there are now more than 40 types of lymphoma, all of which demand separate approach; but in segregating so many, the pathologists have actually lumped two together. Small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL) are regarded by pathologists as a single entity.
From a pathologist’s point of view they are the same disease. When CLL appears in the lymph nodes, the histological pattern is that of SLL, and when SLL eventually appears in the blood, as it does in 25% to 50% of cases, the picture is that of CLL. Diagnostic lymphocyte markers are the same: CD5+, CD19+, CD23+, weak surface Ig, weak CD79b, and FMC7 negative.
However, from the clinician’s viewpoint they are different. By definition, SLL does not appear in the blood. SLL requires enlarged lymph nodes with the same tissue morphology and immunophenotype as CLL with no cytopenias due to bone marrow infiltration and fewer than 5 x 109/L peripheral blood B cells. CLL on the other hand must have more than 5 x 109/L peripheral blood B cells and need not have any lymph node enlargement.
The WHO insists that CLL and SLL are a single disease at different stages. Thus by Ann Arbor staging, CLL is always stage 4, since by definition it is extra nodal. SLL may be stage 4, if there is bone marrow involvement (more than 30% small lymphocytes in the marrow), but may also be stage 1, 2 or 3 depending on how many groups of lymph nodes are involved and whether of not the disease is confined to one side of the diaphragm.
The difference this makes is that stage 1 or 2 lymphomas are potentially curable by involved field or extended field radiotherapy with 80% freedom from relapse in stage 1 and 62% freedom from relapse in stage 2 at 10 years.
For advanced stage SLL treatment recommendations are exactly the same as they are for CLL; the patients should be managed by watchful waiting until certain criteria apply. The only difference from the CLL criteria is the lymphocyte doubling time, which clearly does not apply. Just as with CLL, if the size of the abdominal glands is the criterion for beginning treatment then these need to be measured carefully, which unfortunately means a CT scan. Oftentimes this can be avoided by first attempting to detect them with abdominal ultrasound. Only when they look like having a longest diameter of 10cm need the final decision be made with CT scan measurements.
FCR is now thought to be the best treatment for CLL if the patient is robust enough to manage it. The same is true for SLL.
Is it known why SLL behaves differently to CLL? Not completely, but we do have some clues. Lymphocytes move in response to chemicals called chemokines. We know that CLL cells have more chemokine receptors than SLL cells.
It should not be assumed that all cases of CLL were once cases of SLL. We know that many cases develop from monoclonal B cell lymphocytosis, which is stage 4 from the outset. Probably no more than 10% of cases start in a single lymph node.