Splenic Marginal Zone B-cell Lymphoma/Splenic Marginal Zone Lymphoma (also known as splenic marginal zone B-cell lymphoma) is one of a family of indolent B-cell lymphomas that remain incompletely characterized. These lymphomas can be globally classified into mucosa-associated lymphatic tissue (MALT) lymphoma, also known as extranodal marginal zone lymphoma, and the nonmucosa-associated lymphatic tissue (non-MALT) marginal zone lymphomas, of which there are two: nodal marginal zone lymphoma (NMZL) and splenic marginal zone lymphoma (SMZL) [rx,rx].
Splenic marginal zone lymphoma (SMZL) is an indolent small B-cell lymphoma involving the spleen and bone marrow characterized by a micronodular tumoral infiltration that replaces the preexisting lymphoid follicles and shows marginal zone differentiation as a distinctive finding.
- Marginal zone lymphoma of the spleen
- Marginal Zone Lymphoma of Spleen
- Marginal Zone Lymphoma of the Spleen
- Marginal zone lymphoma of the spleen; SLVL; SMZL
- Splenic Lymphoma with Circulating Villous Lymphocytes
- Splenic lymphoma with villous lymphocytes
- Splenic Marginal Zone B-Cell Lymphoma
- Splenic marginal zone B-cell lymphoma
- Splenic Marginal Zone B-Cell Lymphoma with Villous Lymphocytes
- Splenic Marginal Zone Lymphoma
- Splenic Marginal Zone Lymphoma with Villous Lymphocytes; [rx]
Causes of Splenic Marginal Zone Lymphoma
The cell of origin is postulated to be a post-germinal center B-cell with an unknown degree of differentiation.[rx] SMZL is a form of cancer known to be associated with Hepatitis C virus infection
Symptoms of Splenic Marginal Zone Lymphoma
Splenic MZL might not cause any symptoms at all but your doctor might notice that your spleen is bigger than it should be, or find abnormal cells when you have a blood test done for another reason.
In most people, splenic MZL causes enlargement of your spleen. This is called ‘splenomegaly’. Your doctor might notice it when they are examining your tummy (abdomen) during a routine examination. If your spleen becomes very big, you might feel full very quickly when you eat, or get pain or discomfort behind your ribs.
It is important to note that most people with an enlarged spleen do not have lymphoma. The NHS has more information on problems affecting the spleen.
Unlike most lymphomas, splenic MZL does not usually cause swollen lymph nodes.
Some people with splenic MZL have symptoms caused by lymphoma in their bone marrow (the spongy tissue in the centre of bones where blood cells are made). These include:
- anemia (a shortage of red blood cells), which can make you feel tired or short of breath
- thrombocytopenia (a shortage of platelets), which can cause you to bruise or bleed more easily than usual.
- a larger than normal spleen
- low red blood cell count (called anemia)
- low platelet count (called thrombocytopenia)
- a larger than normal liver (in some cases)
Some people experience unexplained weight loss, night sweats or fever. These are known as ‘B symptoms’ and often occur together.
Around 1 in 5 people with splenic MZL produce abnormal antibodies that clump together at lower temperatures. These are called ‘cryoglobulins’. This can lead to many symptoms, including poor circulation or a rash, especially when it is cold.
Diagnosis of Splenic Marginal Zone Lymphoma
Splenic MZL can be difficult to diagnose. It can look similar to other types of lymphoma, such as Waldenström’s macroglobulinemia. It is usually diagnosed using a combination of:
- blood tests to check your blood cell counts and look for abnormal lymphocytes and antibodies in your blood
- a bone marrow biopsy (a test that involves taking a sample of bone marrow, usually from your hip bone) to check for lymphoma cells in your bone marrow.
The blood sample and bone marrow biopsy are examined by an expert lymphoma pathologist. The pathologist also tests the samples for particular proteins that are found on the surface of lymphoma cells. This can help your medical team decide on the most appropriate treatment for you.
If you have an enlarged spleen, your medical team might suggest that you have it removed so it can be tested in a laboratory to help make a diagnosis. This is done by an operation called a ‘splenectomy’. You can live without a spleen but you are less able to fight infections, so you need to take precautions to lower your risk of getting infections. You are likely to have long-term antibiotic treatment.
You also have blood tests to look at your general health, make sure your kidneys and liver are working well and test for infections such as hepatitis C virus.
You have other tests to find out which areas of your body are affected by lymphoma. This is called staging. It usually involves having a CT scan. You might also have a PET scan if your specialist thinks it would be helpful in planning your treatment, although this is less common for marginal zone lymphomas than other types of lymphoma.
You usually have your tests done as an outpatient. It takes a few weeks to get all the results. Waiting for test results can be a worrying time, but it is important for your medical team to gather all of this information in order to plan the best treatment for you.
The relevant markers that define the immunophenotype for SMZL are shown in the adjacent table.[rx] [rx] The lack of CD5 expression is helpful in the discrimination between SMZL and chronic lymphocytic leukemia/small lymphocytic lymphoma, and the lack of CD10 expression argues against follicular lymphoma. Mantle cell lymphoma is excluded due to the lack of CD5 and cyclin-D1 expression.[rx]
Clonal rearrangements of the immunoglobulin genes (heavy and light chains) are frequently seen.[rx] The deletion 7q21-32 is seen in 40% of SMZL patients, and translocations of the CDK6 gene located at 7q21 have also been reported.[rx]
Bone marrow histology
Bone marrow involvement by SMZL is usually in the form of a micronodular, interstitial and, sometimes, paratrabecular infiltrate. A peculiar intrasinusoidal pattern of involvement has also been observed.[rx] In our study on bone marrow histology in a series of 120 marginal zones lymphomas[rx] we observed an intrasinusoidal pattern in 74% of SMZL but also in 57% of nodal marginal zone lymphomas. Exclusively sinusoidal bone marrow localization is infrequent and the detection of a high rate of sinusoidal infiltration in more than one-half of nodal marginal zone lymphomas is also a notable finding because the nosological definition of SMZL with adenopathy and its biological and clinical relationship with ‘true’ nodal marginal zone lymphomas are still mattered of debate.
SMZL express surface IgM and IgD and are CD19+, CD20+, CD22+, CD79a+, FMC7+, CD10−, CD123−, and CD103−; DBA44, CD11c, CD23 and CD5 can be positive in a subset of cases. Cyclin D1/BCL-1 is not expressed, whereas the BCL-2 protein is intensely expressed.[rx] According to the scoring system for chronic lymphocytic leukemia, the scores for most, if not all, cases of SMZL range from 0 to 2, a phenotype not seen in chronic lymphocytic leukemia.[rx]
Studies of immunoglobulin heavy-chain variable genes (IGHV) in SMZL have provided evidence that this entity is heterogeneous with respect to the preferential use of the IGHV repertoire, as well as the mutation load. In a series of 59 patients IGHV1, IGHV3, and IGHV4 gene families accounted for 30%, 56%, and 14% of sequences, respectively. The most frequently used IGHV genes were IGHV1-2 IGHV3-23, IGHV3-30, and IGHV4-34 (n=5). IGHV was not mutated in 25% of the cases.[rx]
The most frequent cytogenetic aberrations in SMZL are deletion of 7q and gain of 3q (nearly one-third of cases). Other cytogenetic alterations are abnormalities +3, +5, +9q, +12q, +18, and +20q.[rx]
We performed a genome-wide array comparative genomic hybridization at high resolution in 34 patients with SMZL. The most frequent copy number alterations involved chromosomes 7 and 17 (21% and 24%, respectively). The unmutated status of the IGVH gene was related to del(7q) and dup(12q). The high-risk group identified according to the prognostic score for SMZL was associated with del(7q) and del(17p).[rx]
Treatment of Splenic Marginal Zone Lymphoma
Frontline therapy for MZL differs greatly based upon the subtype and underlying etiology. For example, a significant proportion of patients with HCV and EMZL will note the regression of the lymphomatous process after undergoing antiviral treatment for HCV infection. [x,rx–rx] Thus, antiviral therapy for HCV is recommended for all cases of MZL associated with HCV infection.
Alkylating agents and purine analogs have been used as have many chemotherapy combinations such as cyclophosphamide, vincristine, and prednisone (CVP); cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), and fludarabine and cyclophosphamide (FC).[rx, rx, rx, rx] About two-thirds of patients do not respond to first-line treatment with chlorambucil.[rx]
Radiotherapy uses high-energy rays to destroy cancer cells while doing as little harm as possible to normal cells. You may have low doses of radiotherapy to the spleen. This treatment may be used if the enlarged spleen is causing symptoms, but you are not well enough to have surgery or chemotherapy.
Rituximab as monotherapy is effective in SMZL with results similar to splenectomy; it has the potential to provide better responses and has less toxicity compared to chemotherapy.[rx] Rituximab has little impact on the quality of life, has reduced risk of infections, seems to induce durable remissions, and can be used again at relapse.[rx, rx, rx, rx] Clinical and laboratory responses are fast, with improvement in blood counts in about eight weeks.[rx]
Some studies report inferior outcomes of rituximab monotherapy compared to splenectomy, but in non-randomized retrospective clinical there may be a bias of selecting younger and fitter patients for splenectomy.[rx]
Treated with rituximab 375 mg/m2 in an induction phase (weekly for six weeks) followed by a maintenance phase with rituximab every two months for one to two years. The complete response (CR) rate after the induction phase was 45%, unconfirmed CR was 26% and partial response was 24%. The 5-year overall survival and progression-free survivals were 92% and 73%, respectively (p-value <0.001)[rx]. There are other regimens using rituximab; weekly for four weeks with or without maintenance as reported[rx]. The best regimen, whether to use maintenance or retreatment at relapse, is also areas that need to be clarified.
Rituximab with chemotherapy
The aforementioned chemotherapy options are used alone or with rituximab. Purine analogs are more toxic and should be reserved for refractory or relapsed cases. Fludarabine has high response rates, with CR in 70% of cases and progression-free survival of 4.7 years.[rx, rx] A combination with Cladribine increased the CR from 21.4% to 62.5%, and four-year progression-free survival from 52.4% to 83.4%.[rx]
Treatment of patients with splenic marginal zone lymphoma and hepatitis C
Patients with hepatitis C who do not require an immediate cytoreductive treatment should receive first-line antiviral treatment with pegylated alpha-interferon and ribavirin because a CR of SMZL occurs in about 75% of the cases.[rx, rx]
Role of ibrutinib in MZL – is it ready for primetime?
The importance of the role played by BCR signaling in the development of MZL cannot be undermined.[rx,rx] BTK plays a key role in the BCR signaling pathway and has been shown to be involved in the formation, survival, and proliferation of malignant B cells.[rx–rx] The efficacy of the Food and Drug Administration (FDA)-approved ibrutinib in other lymphoid malignancies, including chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia is well known.[rx] Given the likely importance of BCR, induced by chronic antigenic stimulation, in the development of MZL,[rx] it was theorized that BTK targeting may play a role in therapy for R/R MZL. A Phase I trial of single-agent ibrutinib in 56 patients with heavily pretreated B-cell malignancies (median number of prior therapies =3) included 4 patients with R/R MZL; 1 patient sustained a partial response and 3 had stable disease,[rx] thus opening the window for further studies.
Splenectomy was the therapy of choice for decades and is still frequently used, although there is a tendency to prescribe rituximab monotherapy upfront, as most patients are old and with co-morbidities.[rx, rx, rx, rx, rx] Laparoscopy should be preferred whenever possible in patients with advanced age or comorbidities.[rx]
Although marrow involvement is not treated, splenectomy allows quick remission of the symptoms of hypersplenism and cytopenias, such as a significant reduction of circulating lymphocytes in 90% of patients. Regarding clinical improvement, in a series report, seven patients (25%) had increases in bone marrow infiltration by pathological cells, there was a modification of the pattern in five of them.
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