Abstract

Marginal Zone B-cell Non-Hodgkins Lymphoma (NHL) is a type of lymphoma that affects B-cells in the marginal zones of various areas. Marginal zone lymphomas are slow growing and make up about 12% of all B-cell NHL. The median age for diagnosis is 65 years old and is primarily present in the stomach, intestines, salivary glands, lung, thyroid gland, lacrimal gland, conjunctiva, bladder, kidney, skin, soft tissue, thymus gland, and breast. The three types of marginal zone lymphomas include extranodal marginal zone lymphoma (MALT), nodal marginal zone lymphoma, and splenic marginal zone lymphoma. Marginal zone lymphomas are those that develop in the marginal zone or edge of the lymphoid tissue where B-cells are located. All marginal zone lymphomas are low-grade B-cell NHL. Nodal MZL makes up less than 2 in 100 NHL cases, MALT lymphoma makes up 1 in 13 NHL cases, and splenic marginal zone NHL makes up less than 2 in 100 NHL cases. Symptoms tend to vary from each individual patient and are often not enough to make an immediate diagnosis, as this cancer may have similar symptoms to other diseases. Prognosis and treatment are dependent on the location of the cancer and the stage of diganosis.

Mechanism/Pathophysiology

Marginal cell lymphomas are likely derived from cells located in the nodal zone or splenic marginal zone. The cells are derived from B memory cells in the post germinal area and IgM+ or IgD-. It is common to find high LDH levels and serum b2-microglobulin in these individuals. Marginal zone lymphomas generally lack markers in order to come up with an overall diagnosis. CD20 antibodies were found to be present in 100% of the cases, CD43 antibodies were present in 24% of the cases, BCL2 antibodies were present in 43% of the cases, follicular colonization was present in 27% of the cases, CD23 antibodies were present in only 5% of the cases, increased polyclonal plasma cells were present in 8% on the cases, monoclonal plasma cells were present in 31% of the cases, kappa antibodies were present in 44% of the cases, and Lambda antibodies were present in 56% of the cases.

Symptoms | Nodal Marginal Zone B-cell NHL

Individuals with this type of cancer experience almost no symptoms at all.

- Painless Lymphadenopathy

- Fatigue

- Weight loss

- Fevers

- Night sweat

Symptoms | Extranodal Marginal Zone B-cell NHL | Non-Gastric MALT

Most individuals with non-gastric MALT have no symptoms

- Symptoms depend on where the cancer originates:

- Mass in the salivary gland

- Redness and sensitivity of the eye

- Mass in the thyroid

- Problems swallowing

- Cough

- Shortness of breath

- Fever

- Weight loss

- Red-brown discoloration of the skin

Diagnosis | Nodal Marginal Zone B-cell NHL

Nodal MZL is generally diagnosed by taking a biopsy of the affected tissue. This subtype is difficult to diagnose due to its similarity to other types of lymphoma. In order to determine the correct type of lymphoma and stage it accurately, the physician will also need to do a physical exam, blood tests to determine blood cell counts, a CT scan, and/or a PET scan. A PET scan is the most important in planning a course of treatment. A bone marrow biopsy and aspiration test may also be ordered to test for lymph node involvement, which is found in 30-50% of cases.

Diagnosis | Extranodal Marginal Zone B-cell NHL of MALT

In order to diagnose MALT, a biopsy is needed from the affected tissue. If the abnormal tissue is suspected to be in the stomach or bowel, an endoscopy is done in order to get the biopsy. This requires either a gastroscopy or colonoscopy. If the lymphoma is thought to have spread to other areas in this region, an ultrasound scan is often done at the same time. If the abnormal tissue is thought to be in the lungs, a bronchoscopy is ordered.

In order to determine the correct type of lymphoma and stage it accurately, the physician will also need to do a physical exam, blood tests to determine blood cell counts, a CT scan, an MRI and/or a PET scan. A PET scan is the most important in planning a course of treatment.

A bone marrow biopsy may be ordered to test for lymph node involvement. If the lymphoma is in the stomach, the physician will test for H.pylori infection through a stool sample. This infection would be necessary to treat in conjunction to treating the cancer.

Diagnosis | Splenic Marginal Zone B-cell NHL

Splenic MZL is difficult to diagnose and can look similar to other types of lymphoma. Tests include a physical examination, blood tests to determine overall health and detect infections (ex. hepatitis C), a bone marrow biopsy, CT scan, and a PET scan. Sometimes a splenectomy is necessary during the diagnosis process in order to determine the exact type of lymphoma. If the spleen is removed, you will be at a larger risk of infection.

Risk Factors

There is no known cause for any type of Marginal Zone non-Hodgkins lymphoma, but it occurs when the body produces large amounts of abnormal lymphocytes.

Factors that may increase an individuals chance of developing nodal MZL are being over the age of 60 and having been infected with hepatitis C virus. Factors that may increase an individuals chance of developing MALT lymphoma include being over the age of 50, having an autoimmune condition (rheumatoid arthritis, Hashimoto's thyroiditis), and long lasting chronic inflammation due to infection (H.pylori, Sjogren syndrome, chlamidia infection, Borrelia infection, Campylobacter jejuni infection). Factors that increase an individuals risk of developing splenic MZL include the hepatitis C virus, Epstein-Barr virus, malaria, Sjogren syndrome, and lupus.

In order to reduce the chances of developing MZL, an individual can decrease their exposure to the possible risk factors.

Treatment and Prognosis | Treatment | Nodal Marginal Zone B-cell Lymphoma

Treatment is dependent if the lymphoma is causing issues in regards to the overall health of the individual. Since this a slow moving cancer, many patients start treatment when the symptoms appear. If the individual tests positive for hepatitis C, then anti-viral treatment is suggested since it will often get rid of the lymphoma as well. If further treatment is required the options include chemotherapy, monoclonal antibodies, and/or radiation. Radiation therapy is used for stage I and II nodal marginal zone NHL. Clinical trials show success in treatment when using drugs such as bendamustine and lenalidomida in combination with rituximab.

Treatment and Prognosis | Treatment | Extranodal Marginal Zone B-cell Lymphoma of MALT

The original route of treatment for MALT is antibiotics to treat an underlying infection such as H.pylori. H.pylori is directly related to the development of this lymphoma. Since most patients respond well to this treatment, then no further treatment is needed. If the lymphoma is not linked to an infection, then radiotherapy and chemotherapy are needed. If the disease is more advanced, then immunoradiotherapy with chemotherapy will be needed. Among the common first-line treatments are bendamustine plus rituximab and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Recently, antibiotic therapy such as doxycycline has been shown to be effective in marginal zone lymphoma that affects the area around the eye ("ocular adnexal marginal zone lymphoma").

Treatment and Prognosis | Treatment | Splenic Marginal Zone Lymphoma

Treatment is often dependent on if the lymphoma is causing issues in regards to the overall health of the individual. Since this a slow moving cancer, many patients start treatment when the symptoms appear. If the individual tests positive for hepatitis C, then anti-viral treatment is suggested since it will often get rid of the lymphoma as well. A splenectomy is generally taken as the initial form of treatment and used to confirm the diagnosis. Further treatment of this cancer is generally not needed until years later and may include chemotherapy, antibody therapy, and/or radiotherapy if the spleen was not initially removed.

Treatment and Prognosis | Diet and Activity

Generally individuals with MZL can follow a normal diet. Neutropenic individuals are instructed to avoid raw fruits and vegetables. Individuals with thrombocytopenia or neutropenia should use toothette swabs to clean teeth, avoid shaving with razors, avoid intramuscular injections, and should instruct all individuals to wash their hands if they are near by.

Treatment and Prognosis | Prognosis | General Prognosis Factors

An individuals prognosis can be based on the Ann Arbor Staging System. If an individual is diagnosed with Stage I marginal zone B-cell NHL, this indicates that there is involvement of a single lymph node region and/or involvement of a single extra-lymphatic organ. Stage II indicates that two or more lymph node regions on the same side of the diaphragm and/or involvement of an extra-lymphatic organ or site and one or more lymph node on the same side of the diaphragm. Stage III indicates involvement of lymph nodes on both sides of the diaphragm, splenic involvement, and extra lymphatic site involvement. Stage IV indicates involvement of more than one extra lymphatic organ or tissues without lymph node involvement. If symptoms such as fever, night sweats, and more than a 10% weight loss are experienced within the first six months, this is characterized by a "B" for present. If these symptoms are absent this is characterized by an "A" for abscent. Extra-nodal sites are characterized as follows: marrow (M+), lungs (L+), liver (H+), pleura (P+), bone (O+), and skin and subcutaneous tissue (D+).

Nodal MZL not only develops at a very slow rate but often relapses in individuals. These individuals often survive for a long time with treatment at various points in their life to keep the cancer at bay. MALT lymphoma also develops at a slow rate and is usually treated successfully even when present in various areas of the body. Splenic MZL also develops at a slow rate but is usually incurable. Even though it is not generally cured, it can be managed for many years

It is important to note that the prognosis of individual cases varies and further information will be available through a physician.

Recent Research

Various new drugs such as B-cell receptor signaling blockers and ibritumomab tiuxetan (Zevlin) are being tested in clinical trials for MZL. These trials are important in determining dosages and safety of the drugs in study. As of January 19, 2017, the FDA approved the first ever targeted drug for MZL, ibrutinib. This drug works by inhibiting Bruton's tyrosine kinase (BKT), which is able to send signals to the nucleus for survival. In other words, it slows the growth of B-cells.

Even though a splenectomy is still seen as a first line of treatment for splenic marginal zone lymphoma, recent studies show that the drug Rituximab could also be successfully used as a first line of treatment. In patients with extra-nodal MALT, it was found that survival increases if the cancer was treated when found early and MALT found in the stomach had the lowest incidence rate of relapse. This indicates that localized therapies are very effective in the treatment of extra-nodal marginal zone lymphoma when found early in early stages.

Cause

It has been known to be related to a translocation between chromosomes 11 and 18; t(11,18).

Diagnosis | Classification

There are three types of marginal zone lymphoma:

Extranodal marginal zone lymphoma or mucosa-associated lymphoid tissue (MALT) lymphoma is the most common form of marginal zone lymphoma. It occurs outside the lymph nodes, This form of lymphoma makes up about nine percent of all B-cell lymphomas.

In many cases of MALT lymphoma, patient has a previous medical history of inflammation or autoimmune disorders. For example, Helicobacter pylori (H. pylori), a microbial pathogen linked to chronic stomach inflammation, and has been associated with a significant portion of stomach MALT lymphoma cases.

Nodal marginal zone lymphoma (sometimes called monocytoid B-cell lymphoma) occurs within the lymph nodes and accounts for about two percent of all B-cell lymphomas.

Splenic marginal zone lymphoma occurs most often in the spleen and blood. It has been associated with Hepatitis C. This form of lymphoma makes up about one percent of all B-cell lymphoma.

Treatment

The type of treatment selected depends on stage of disease, the age of the patient, the patient's overall health, any signs or symptoms related to the lymphoma, and the location of the disease.

Treatment Options for Gastric MALT

For gastric MALT lymphoma, the initial treatment is antibiotic therapy to get rid of Helicobacter pylori, which is typically given for two weeks. Approximately 70 percent to 90 percent of patients respond to antibiotic therapy, and approximately half of the patients require no further treatment. If the lymphoma relapses after antibiotic therapy, there are many additional treatment options available, including (in alphabetical order):

- Bendamustine

- Bortezomib

- Fludarabine

- Radiation (low dose)

- Rituximab

- Surgical excision

Treatment Options for Non-gastric MALT

Non-gastric MALT can appear in a variety of areas throughout the body. Therefore, treatment is usually based on the exact location and extent of spread. Treatment typically includes surgery for certain sites (lung, breast) or radiation therapy with or without chemotherapy. More advanced disease usually includes immunoradiotherapy with chemotherapy. Among the common first-line treatments are bendamustine plus rituximab and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Recently, antibiotic therapy such as doxycycline has been shown to be effective in marginal zone lymphoma that affects the area around the eye ("ocular adnexal marginal zone lymphoma").

Treatment Options for Nodal Marginal Zone Lymphoma

Because nodal marginal zone lymphoma is most often a slow-growing disease, doctors may defer treatment until symptoms appear, an approach called "watch and wait" or "watchful waiting." When treatment is necessary, options include radiation therapy, chemotherapy, and other treatments commonly used in other types of slow-growing lymphomas, such as follicular lymphoma.

Treatment Options for Splenic Marginal Zone Lymphoma

Several treatment options exist for splenic marginal zone lymphoma. Some patients undergo surgical removal of the spleen (splenectomy) or, for those patients who are not surgical candidates, low-dose radiation of the spleen. Other patients may receive rituximab, a monoclonal antibody, with or without chemotherapy.

Research

Several new drugs and drug combinations are being studied in clinical trials for marginal zone lymphoma and other slow-growing lymphomas, including:

- B-cell receptor signaling blockers

- Ibritumomab tiuxetan

Both are CD5 and CD10 negative