Marginal zone lymphoma

The third most common B cell non-Hodgkin’s lymphoma:after diffuse large B cell lymphoma and follicular lymphoma.

A heterogeneous group of diseases.

Arises from post-germinal marginal zone B cells that have similar immunophenotypes.

Arises from the cooperation of immunologically driven and genetic changes in a multi step process.

Generally associated with favorable long-term survival.

Marginal zone lymphoma is a serious disease diagnosed in more than 2000 patients every year in the US, with no clear standard of care. 

Consists of three different entities: extranodal MZL of the mucosal-associated lymphoid tissue (MALT), nodal marginal zone lymphoma, and splenic marginal zone lymphoma.

Three different types differ in prognosis and outcomes, therefore identification of clinical characteristics is important before determining therapy.

Organ specific inflammation generates an immune response, which preferentially  expands B cell clones  and reactive B cell receptors imbedded in the immune microenvironment.

Lymphoma progression is sustained by the addition of molecular lesions in pathways that were previously activated by the inflamed microenvironment, deregulating the pathway so that the tumor is no longer dependent on the microenvironment.

The incidence has been increasing 1% per year, partly reflecting improved diagnosis.

There has been a reduction in cases of extranodal MZL subtypes an increase in cases of splenic MZL.

Differences in temperature and geographic features of MZL‘s may reflect predisposing conditions such as Helicobacter pylori and hepatitis C infections.

Among extranodal MZL‘s there has been a decrease in gastric MZL‘s, probably due to a lower prevalence of H. pylori.

The incidence of MZL‘s increases exponentially with age.

MZL are more frequent in males, with the exception of extranodal  MZLs that arise in salivary and thyroid glands, which  may harbor autoimmune conditions that occurs more commonly among females.

MZL’s of the lung may have involvement with Achromobacter xylosoxidans a gram negative bacteria with low virulence.

Splenic and nodal MCL‘s have a common genetic background, characterized by a variety of mutations.

Sjogren syndrome and Hashimoto’s thyroiditis arevpredisposing factors for salivary gland and thyroid MZL’s‘s, respectively.

A family history may suggest an inherited genetic factor including alleles of HLA and IGHV loci.

These findings suggest involvement of microbial antigens for auto antigen stimulation in the process of lymphoma genesis.

Examination of tumor tissue biopsy is required for final diagnosis.

Fine needle cytology is not suitable for diagnosis, since small lymphoma cells cannot be distinguished from reactive B cells, and tissue architecture cannot be examined.

Prognosis for MALT lymphoma is better than prognosis for splenic marginal zone lymphoma or nodal marginal zone lymphoma.

Nodal MZL is a primary nodal lymphoma that usually disseminates systemically.

Clonal B cell  lymphocytosis of marginal zone origin is a pre-malignant condition that is incidentally discovered and is characterized by persistent lymphocytosis, bone marrow involvement by cells that are similar to those involved in MCL, and no associated organomegaly.

No diagnostic biomarkers are present for MZL’s‘s.

The prevention or early treatment of pre-disposing infections can avert MZL‘s: treatment of H. pylori and HCV infection may reduce the risk of lymphoma.

Prognosis for MALT is five-year relative survival rate estimated to be 88.7% compared with 79.7% for splenic marginal zone lymphoma and 76.5% for nodal marginal zone lymphoma.

Median survival exceeds 10 years, although the disease does affect life expectancy.

Progression of disease within two years of initial treatment is the strongest prognostic biomarker of reduced survival: patients with relapse of progression within two years, which is approximately 20% of patients,  with MZL’s have a median survival of only 3 to 5 years, whereas life expectancy for the remaining approximately 80% of patients is similar to that  of aged matched general population.

Cutaneous MZL’s‘s have a extremely indolent course

Splenic marginal zone lymphoma expresses B cell antigens CD 19, CD 20, CD 22, and it is typically CD5 negative, CD 10 negative, CD 43 negative, CD 103 negative and CV 25 negative.

A history of chronic infections and autoimmune conditions are commonly associated with MZL‘s.

Chronic H. pyloric gastritis is a predisposing factor for gastric MZL‘s.

Strong evidence suggest association with chlamydia with ocular adnexa MZL‘s, borrelia for cutaneous MZL‘s, Campylobacter for  small intestine MZL‘s, HCV infection particularly when complicated by cryoglobulinemia can proceed nodal and splenic MZL’sas well as extranodal MZls.

It is essential to treat infection in patients with Helicobacter pylori positive gastric MZL and in those patients with hepatitis C virus and any MCL.
Active surveillance is recommended for patients with advanced stage disease who are asymptomatic, since treatment delay does not impair survival.
In hepatitis C infection, the hepatitis should be treated and cured.
H. pylori should be eradicated in all patients with gastric MZL.

For patients with localized gastric MCL, the initial treatment should be solely H. Pylori  eradication which induces lymphoma remission and leads  to long-term control of clinical disease in 3/4 of such patients; remission develop slowly and can take up to one year.

Radiotherapy to the stomach and perigastric nodes provides excellent disease control in localized H. pylori negative and in patients who do not have lymphoma regression after antibiotic therapy.

Radiotherapy results in complete remission and cure in almost all patients with relapses in only 5 to 10% of patients over time.

Gastrectomy must be avoided in H. pylori  positive gastric MCL‘s, as it is associated with increased morbidity  and recurrence rates.
Standard first line therapies include involved site radiotherapy for localized disease.
Localized fields are better than wide fields, especially for parotid MALTs.
Nodal MZL‘s the pattern of treatment is similar to gastric Maltomas:  limited field radiation, chemo immunotherapy for advanced stage disease and rituximab for elderly or infirmed patients.
Advanced stage MZL‘s are not curable with conventional treatment.
The indication for treatment in splenic MZL‘s includes progressive or symptomatic splenomegaly and progressive cytopenia.
Treatment as indicated in patients with advanced stage extranodal or nodal MZL if they have high tumor burden.

((Umbralisib))agent is specifically indicated for adult patients with relapsed/refractory MZL who have previously received at least 1 anti-CD20–based regimens.

Clinical manifestations of MZL‘s are multifaceted with patients with extranodal disease presenting with symptoms involving tissues of the affected site.

Patients with gastric MCL‘s present with epigastric pain, weight loss, or G.I. bleeding.

Immunoproliferative small intestinal disease is manifested with diarrhea, abdominal pain, and malabsorption.

Ocular adnexal MCL‘s present with masses or eye redness.

Patients with salivary and thyroid gland MCL present with slowly growing in painless lumps.

Cutaneous MCL‘s manifest as red as or violaceous skin papules, plaques or nodules usually located on the trunk or arms.

Lung MCL‘s are generally asymptomatic.

Clonal B cell lymphocytosis, splenic MZL, and nodal MZL are usually disseminated disorders.

Patients may be asymptomatic or have  incidental  findings of lymphocytosis, splenomegaly, or painless peripheral adenopathy.

Patients may have massive splenomegaly or bulky lymphadenopathy.

Systemic symptoms such as fever and night sweats are rare.

Serum immunoglobulin paraprotein is found in approximately 30% of patient who is splenic MCL or clonal B cell marginal zone lymphoma.

20% of patients with splenic MCL have a paraneoplastic auto immune manifestation.


Symptomatic advanced stage MZL‘s are best  treated with Rituximab based approaches.

Rituximab in combination with chlorambucil, bendamustine, doxorubicin are all efficacious.

Ibrutinib has an overall response rate of 48% when given as a continuous therapy with the median progression free survival of 14 months.

Splenic MZL  performs the best of all subtypes with Ibrutinib, with the median progression free survival of 19.4 months.

Splenectomy has been replaced by rituximab in patients with splenic MCL.

Lenalidomide is typically given in combination with rituximab with response rates ranging from 54 to 80% and progression free survival estimating 17 months to two years.


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