Splenic marginal zone lymphoma (SMZL)

SMZL is one of the diseases that get misdiagnosed as CLL. Before we had flow cytometry there was some excuse for this, but increasingly it is an error that oncologists ought to know about.

I remember attending a meeting at a country house near Windsor in the 1980s. All the great CLL names were there: Binet, Rai, Catovsky, Montserrat, Caligaris-Cappio, Galton, Hansen, Kimby and many others. The French group was talking about a group of cases that they staged as A2, who had a very good prognosis. This meant that they had enlarged spleens but no lymph nodes to feel. We now know that these were cases of SMZL.

David Oscier joined me in Bournemouth in 1981. One of the first things he did was to set about establishing a center of excellence for CLL cytogenetics. It was he who discovered the 13q deletion in CLL. Among the things that he discovered were a group of patients who despite having a complex karyotype, often involving the long arm of chromosome 7, were very benign. In retrospect, these patients had SMZL.

I remember one patient whose name was the same as a famous poet from World War One, who had both CLL and sideroblastic anemia. His lymphocytes were rather large and angry looking, even having small 'hairs' at one end. Despite this his disease was entirely benign. Another patient, a woman who had been with me for many years, has some odd features. She had a monoclonal protein in her serum. She responded quite well to chlorambucil, but she developed a bad case of shingles, affecting the skin of the back of the leg, but, most unusually, also affecting the muscles, a case of the very rare 'motor shingles'. She is the only patient I have seen to have developed acute myeloid leukemia after treatment with chlorambucil. Another patient I remember also had a small monoclonal protein in his serum, but as a consequence developed intermittent attacks of abdominal pain and swelling of the lips and mouth so as to interfere with his breathing. Despite having the protein that acts as an inhibitor or C1 esterase, he had no C1 esterase activity in his blood. In retrospect, all three of these patients had SMZL.

SMZL, then, is a condition that mimics CLL but one that has important differences.

The WHO classification recognizes three types of marginal zone lymphoma: Extranodal marginal zone lymphoma (which occurs in the mucosa associated lymphoid tissue [MALT lymphomas] such as occur in the stomach and are often associated with helicobacter pylori), Nodal marginal zone lymphoma (sometimes called monocytoid B cell lymphoma) and SMZL. We can ignore the other two, which simply confuse matters. SMZL was not differentiated from CLL in previous classifications.

In some cases of SMZL the lymphocytes have small hairs or 'villi' sticking out from the surface, especially at one and of the cell, which was why some people call it splenic lymphoma with villous lymphocytes (SLVL), but these are not always seen, even in the same case on different occasions, which is why I prefer the SMZL name.
The hairs are the cause of the resemblance to hairy cell leukemia, but in real life they are so different that nobody should confuse them. The SMZL cells are rather larger than CLL cells and have obviously more cytoplasm

The biggest distinction between CLL and SMZL is CD5. Anything that seems to be CLL yet is CD5 negative is likely to be SMZL.

SMZL is a lymphoma of small lymphocytes that seems to arise in the spleen. They replace the splenic white pulp germinal centers, wipe out the follicular mantle, and merge with the marginal zone of larger cells, which include some larger blast-like cells. Both small and large cells invade the red pulp and the lymph nodes at the hilum of the spleen are involved. The bone marrow and blood are also usually involved, but the lymph nodes only very rarely.

SMZL is quite rare, comprising about 1% of lymphomas. It usually presents with an enlarged spleen , or as an incidental finding of a high white count. About a third of patients have a monoclonal immunoglobulin in the blood and this has led some people to think that it overlaps with Waldenstrom's macroglobulinemia, but the monoclonal protein is never very high so as to cause hyperviscosity, nor does it usually cause hypogammaglobulinemia by depressing the normal immunoglobulins.

The immunophenotype is CD19+, CD20+, surface Ig bright, CD79b+, but CD5 neg, CD23 neg, CD43 neg.

The chromosomes are abnormal in more than half of cases with deletion of the long arm of chromosome 7 missing in about 40%. the deletion is between 7q21-32 and is thought to involve the CDK6 gene. Occasional the t(11;14) translocation has been reported, but these cases seem to be cases of mantle cell lymphoma that have been misdiagnosed.

Most cases have mutated IgVH genes, though occasional unmutated cases have been reported. There are some suggestions that this may be a prognostic factor in SMZL, just as it is in CLL. But the prognosis is usually much better than in CLL, with most cases being very indolent. Anemia or thrombocytopenia when they occur are often caused by hypersplenism (an overactive spleen) and are best treated by splenectomy. In retrospect, the first case of this condition that I saw was in 1969. An old woman with lymphoma was apparently cured by splenectomy.

So, the first thing you do with SMZL is get the diagnosis right because it is so error prone. The second thing is to watch and wait. If treatment becomes necessary then splenectomy is first choice. Chemotherapy comes bottom of the list, but the type of chemotherapy to use is not evidence based, and most people would follow the same practice that they use in CLL.

Complications of SMZL include a Richter-like transformation and acquired angioedema.