Tuesday, September 26, 2006

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.


Chaya said...

Dear Terry:

Thank you for this nice description of SMZL. I am sure you are familiar with the link between SLVL (aka SMZL) and hepatitis C virus that has been proposed in the last few years. The two articles in Blood and New England Journal of Medicine speak of effective treatment of the lymphoma by way of treating the viral infection.



In the 2005 Blood article, 18 patients who had SLVL and tested positive for hepatitis C were treated with interferon alone or in combination with ribavirin, standard therapies for hepatitis C viral infection. 78% of the patients got complete clearance of their lymphoma, when they achieved clearance of the virus. Two more patients got full lymphoma clearance, even though they got only a partial response as far as the virus is concerned. This is amazing stuff! Cure the cancer by killing the viral driver of the cancer. Both this paper and the NEJM paper underscore the importance of hepatitis C virus in the genesis and progression of the SLVL, and that antiviral treatment for SLVL patients who test positive for hepatitis C is a good therapy choice. That preamble brings me to my two questions:

(1) Do you have further comments on SZML (SLVL) in regard to it possible initiation and progression driven by hepatitis C viral infection?

(2) There has been recent flurry of interest in the role of Epstein-Barr virus, and the impact it may have in CLL prognostics. Our very non-scientific poll among our members suggests a very disproportionate percentage of CLL patients have had clinically diagnosed EBV driven mononucleosis as children or young adults. CLL patients who had EBV encoded RNA (EBERs) in their bone marrow have been shown to have significantly poorer prognosis, and higher risk of Richter’s transformation. We addressed some of these issues in a recent article on our website:


My question is this: would it be possible to control the CLL by treating the dormant EBV infection in these patients, similar to the anti-viral treatment that helped the SLVL patients? Has interferon therapy ever been tried in EBER positive CLL patients, or those with documented clinical mononucleosis in their past, possibly in combination with other possible anti-viral agents? Thanks for all your efforts on our behalf.


Terry Hamblin said...

The type of SLVL with cryoglobulinemia described by the French group is quite distinct from the SMZL that we usually see. Hepatitis C is quite rare in the UK and none of my cases have been Hep C positive.

Interferon does have modest effects on early stage CLL whether or not it is EBV positive. The results have never been thought to be worth the side effects though.

I think that the association of EBV and CLL is speculation at present.

Hal Skye said...

Dear Dr. Terry.--re your recent blog on SMZL. In 2003 I went to MDACC for one of my several 2nd opinions. Could you comment on an excerpt from their report: "Flow cytometry immunophenotyping demonstrates that the lymphocytes coexpress CD19 and CD5, and are also positive for CD23, CD20 (strong), FMC-7, IgMD, CD38, CD79b, CD52, CD11c, and partial positive CD22 (50%). CD10 was negative. The neoplastic cells are kappa light chain restricted. Although CD5 and CD23 are positive in this case, presence of enlarged spleen and strong expression for CD20, immunoglobulin, FMC-7 and CD79b are in favor of SPLENIC MARGINAL ZONE LYMPHOMA. We performed immunostain for cyclin D1 that was negative." So Dr.Terry--what is the bottom line in your opinion? Could I be SMZL? Could I be CLL as all the other Oncs & pathologists have deduced? Do I have to be retested in a more esteemed cancer center? Could I be a one of a kind hybrid case---CLL/SMZL, Thank you for any info. you can direct my way as to how to proceed.

Terry Hamblin said...


Almost all diseases have fuzzy edges. I would regard you as having CLL. The hardest evidence for CLL - the positive tests for CD5 and CD23 - rarely show up on SMZL, while the hardest evidence for SMZL - stronger CD20, FMC7, CD22 - are seen in cLL, especially if there is also trisomy 12 or del 11q. Big spleens occur in either, though if tou have a big spleen without lymph node enlarement and a monoclonal paraprotein then I might be swayed the other way.

If treatment is necessary then consider splenectomy. If it is SMZL then not only would it be very helpful clinically, but the histology of the spleen would help to confirm the diagnosis.

carla rapaccini said...

Dr Hamblin, my husband at first
was misdiagnosed with CLL, then
with SMZL.He underwent splenectomy
but unfortunately the surgeon found a second cancer (adenocarcinoma colon, stage T3 ) below the
lymphomatous spleen.He is now
undergoing adjiuvant chemotherapy
for cc with oxaliplatin and fluorouracil.His oncologist does not know anything about SMZL.
Could this chemo drug be detrimental for the lymphoma?

Terry Hamblin said...

Platinum compaounds like oxiplatin are quite useful in lymphomas. I suppose he was lucky in that had he not had the surgery, the colon cancer might not have appeared until it was beyond treatment.

carla rapaccini said...

Well, my husband's option for
splenectomy allowed discovery
of a dangerous neoplasia at less
advanced stage...
I want to add that my husband tested negative for hepatitis C, but here in Italy some doctors in a study (L.Arcaini et al. "Splenic
marginal zone lymphoma:a prognostic
model for clinical use") found that
HCV seroprevalence in splenic MZL
is 19 percent and this percentage is considerable despite the high seroprevalence of HCV infection in
the Italian population. However the association of HCV infection
with splenic MZL has not been found
in other series.

Anonymous said...

Dear Dr. Hamblin:

Are you familiar with treatment of SMZL with rituximab? I have had the four-week infusion regimine and am about to have my third monthly session. Thus far, my WBC has diminished from 60,000 to 12,000 (as of a month ago), and my spleen has shrunk from extended to lower abdomen to two fingers below the rib cage. My platelet count has risen from 90 to 120 (as of a month ago). And on the whole, I feel much better and have more energy. I was originally diagnosed with CLL in 1984, corrected to SMZL in 2003. I urge further consideration of use of rituximab for SMZL. (I live in upstate New York, USA, and receive treatment in Syracuse, NY.)

Terry Hamblin said...

Yes, this is what I would expect. CD20 is bright on SMZL cells. Of course it is such a rare disease that there are no formal clinical trials of any size.

Avril Cudmore said...

Dear Dr Hamblin
I was diagnosed with Splenic Marginal Zone Lymphoma in May this year. I presented with massive splenomegaly,Neutropenia and thrombocytopenia. I had my spleen removed. I have bone marrow involvement but fairly negligible at this stage. My problem is that I have lymph node involvement with lymphadenopathy in my mediastinum, pre and para aortic, porta hepatis, epicardiac fat and my left neck. the neck is proving to be a problem as it is between the jugular vein and carotid artery.I have had this biopsied twice. After the second biopsy it has been reducedin size to to 3.1cms. but cannot be operated on any further because of its position. My haemotologist is proposing a 6 month course of chlorambucil - 1 week on 3 weeks off. Do you have any experience of chlorambucil in this situation - is it the right treatment to follow? I would really appreciate your comment. I cannot find anyone else on cancer support groups e.g.The American Cancer Society who has this lymphoma. I am 64 years old and live in South Africa.

Terry Hamblin said...

Certainly some patients do respond to chlorambucil. Apart from the good response to splenectomy, SLVL responds to the same drugs as CLL. It tends to be a more indolent disease, though.