Splenic marginal zone lymphoma overview

# Overview
Splenic marginal zone lymphoma (SMZL) is rare, indolent B-cell lymphoma that may arise from either pre germinal or germinal/post germinal center replacing the normal architecture of the white pulp of the spleen. Chromosomal aberrations and gene mutations involved in the pathogenesis of splenic marginal zone lymphoma include 7q32 deletion, gain of function 3q, 4q and NOTCH2, TP53, KLF2 and immunoglobulin heavy chain gene. On microscopic histopathological analysis, micronodular lymphocytic infiltration of the white pulp along with biphasic distribution of neoplastic B-cells in the follicles of spleen, mixed pattern of lymphocytic infiltration of the bone marrow and villous lymphocytes in peripheral blood, are the characteristic findings of splenic marginal zone lymphoma (SMZL). Hepatitis C viral antigen is also assumed to be involved in its causation. Splenic marginal zone lymphoma (SMZL) must be differentiated from other B-cell lymphomas such as  chronic lymphocytic leukemia,  follicular lymphoma, and mantle cell lymphoma and unclassifiable splenic lymphomas including hairy cell leukemia variant (HCL-v) and splenic diffuse red pulp small B-cell lymphoma (SDRPL). The incidence of splenic marginal zone lymphoma (SMZL) increases with age; the median age at diagnosis is 65-70 years. Splenic marginal zone lymphoma (SMZL) affects men and women equally. There are no established risk factors. According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening. Low Hemoglobin levels, high lactate dehydrogenase levels, low blood serum albumin levels,  and  genetic mutations in NOTCH2 TP53 genes are associated with poor prognosis. According to the Lugano classification, there are four stages of splenic marginal zone lymphoma (SMZL) based on the number of nodes and extranodal involvement. The most common symptoms of splenic marginal zone lymphoma include fever, weight loss, skin rash, night sweats, chest pain, abdominal pain, bone pain, and painless swelling in the neck, axilla, groin, thorax, and abdomen. Common physical examination findings of splenic marginal zone lymphoma (SMZL) include fever, rash, ulcer, splenomegaly, chest tenderness, abdomen tenderness, bone tenderness, peripheral lymphadenopathy, and central lymphadenopathy. Laboratory tests for splenic marginal zone lymphoma (SMZL) include complete blood count (CBC), blood chemistry studies, cytogenetic analysis, flow cytometry, immunohistochemistry, genetic testing, FISH, PCR, and immunophenotyping. Lymph node or extranodal tissue( spleen, bone marrow) biopsy is diagnostic of splenic marginal zone lymphoma.splenomegaly and lymphadenopathy and other organs involvement may be seen on abdominal ultrasound, CT scan, MRI and PET scan in patients with splenic marginal zone lymphoma (SMZL). Other diagnostic studies include laparoscopy, laparotomy. The optimal therapy for splenic marginal zone lymphoma (SMZL) depends on the clinical presentation of the patient. Asymptomatic patients may be observed closely without any treatment. Splenomegaly related symptoms such as abdominal distension, tenderness, early satiety, bloating and cytopenia due to hypersplenism may be managed with splenectomy but if bone marrow is involved it will persist even after surgery. Splenectomy was considered to be the first line treatment option but studies reported recently that rituximab alone or in combination with chemotherapy is equally effective if not better in terms of complete remission, progression free and overall survival and in addition there is no surgical risk. Studies have also shown that patients who relapsed while on treatment with rituximab, responded well with retreatment. Patients with hepatitis C who developed splenic marginal zone lymphoma (SMZL) have shown tumor regression with antiviral therapy.

# Historical Perspective
The term splenic marginal zone lymphoma (SMZL) was used by C. Schmid in 1992 and is described as separate entity from marginal zone lymphoma in the World Health Organization classification of lymphoid neoplasms in 2001.

# Pathophysiology
The exact pathogenesis of splenic marginal zone lymphoma (SMZL) is not clearly understood but according to some studies chronic immunologic stimulation and certain gene mutations are assumed to be involved. The common chromosomal aberrations and genetic mutations in splenic marginal zone lymphoma (SMZL) includes 7q32 deletion, gain of function mutation in 3q and  NOTCH2, TP53, KLF2 gene mutations. These genes control certain cell regulation pathways that are involved in normal functioning of the cell. Hepatitis C viral antigen has also been assumed to be involved in its pathogenesis. Spleen, bone marrow, lymph nodes, liver and blood may be infiltrated with the tumor and have certain distintive features. On microscopic histopathological analysis, B-cells, villous lymphocytes, and sinus invasion are characteristic findings of splenic marginal zone lymphoma (SMZL).

# Causes
Some studies suggest an association between Hepatitis C and splenic marginal zone lymphoma (SMZL) and assume that it may have some role in its causation.

# Differential Diagnosis
Splenic marginal zone lymphoma (SMZL) must be differentiated from other B-cell lymphomas such as chronic lymphocytic leukemia,  follicular lymphoma, mantle cell lymphoma and unclassifiable B-cell lymphomas including Hairy cell leukemia variant (HCL-v) and splenic diffuse red pulp small B-cell lymphoma (SDRPL) on the basis of cytogenetics, immunophenotyping and morphological as the treatment for these conditions varies.

# Epidemiology and demographics
Splenic marginal zone lymphoma (SMZL) constitutes less than 1% of all non-Hodgkin's lymphomas. Its incidence increases with age. It is found to be more common in caucasians. Splenic marginal zone lymphoma (SMZL) affects men and women equally.

# Risk Factors
There are no established risk factors for splenic marginal zone lymphoma.

# Screening
According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for splenic marginal zone  lymphoma

# Natural History, Complications and Prognosis
Splenic marginal zone lymphoma (SMZL) is a rare, slow growing B-cell lymphoma that is mostly asymptomatic at the time of diagnosis. It is commonly diagnosed at an old age. Patients typically have splenomegaly, lymphocytosis or cytopenias. Bone marrow is frequently involved but lymphadenopathy and liver involvement is rare.There are automimmune conditions that may develop in this conditions such autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, angioedema and von-willebrand disease. It may transform into diffuse large B-cell lymphoma. The prognosis is generally good. Several factors including lymphadenopathy, non-hematopoietic site involvement, histologic transformation affects the prognosis. Low Hemoglobin levels, high lactate dehydrogenase levels, low blood serum albumin levels,  and  genetic mutations such as mutations in NOTCH2, TP53, KLF2 are associated with poor prognosis among patients with splenic marginal zone lymphoma.

# Diagnosis

## Diagnostic Study of Choice
Histological examination of the spleen is considered as a gold standard for the diagnosis of splenic marginal zone lymphoma (SMZL). But as splenectomy is not as frequently performed as it was other diagnostic options are sought which includes histological analysis and immunohistochemistry of the bone marrow biopsy and peripheral blood. Cytogenetic analysis is also helpful in making the diagnosis.

## Staging
According to the Lugano classification, there are four stages of splenic marginal zone lymphoma (SMZL) based on the number of nodes and extranodal involvement.

## History and Symptoms
The most common symptoms of splenic marginal zone lymphoma (SMZL) include fever, weight loss, skin rash, night sweats, chest pain, abdominal pain, bone pain, and painless swelling in the neck, axilla, groin, thorax, and abdomen.

## Physical Examination
Common physical examination findings of splenic marginal zone lymphoma (SMZL) include fever, rash, ulcer, splenomegaly, chest tenderness, abdomen tenderness, bone tenderness, peripheral lymphadenopathy, and central lymphadenopathy.

## Laboratory tests
Laboratory tests for splenic marginal zone lymphoma (SMZL) include complete blood count (CBC), blood chemistry studies, immunohistochemistry, genetic testing, flow cytometry, FISH, PCR, and immunophenotyping.

## Biopsy
Lymph node or extranodal tissue biopsy is diagnostic of splenic marginal zone lymphoma (SMZL).

## CT
CT scan may be helpful in the diagnosis and estimating the extent of tumor spread in splenic marginal zone lymphoma (SMZL).

## MRI
MRI may be helpful in the diagnosis of splenic marginal zone lymphoma (SMZL).

## Ultrasound
Abdomen ultrasound may be helpful in the diagnosis of splenic marginal zone lymphoma (SMZL). Findings on ultrasound abdomen suggestive of splenic marginal zone lymphoma (SMZL) include splenomegaly and lymphadenopathy.

## Other Imaging Studies
PET scan may be helpful in the diagnosis of splenic marginal zone lymphoma (SMZL).

## Other Diagnostic Studies
Other diagnostic studies for splenic marginal zone lymphoma (SMZL) include laparoscopy and laparotomy.

# Treatment

## Medical Therapy
There is no standardized treatment of splenic marginal zone lymphoma (SMZL) The optimal therapy depends on the clinical presentation. Asymptomatic patients may only be observed routinely without any treatment as it is an indolent tumor. Symptomatic patients may treated with either surgery, immunotherapy, chemotherapy, immunochemotherapy or antiviral drugs. Both surgery and immunotherapy are equally effective but recently immunotherapy is considered as a better treatment option as there is no risk of complications that are associated with surgery.

## Surgery
Splenectomy was considered to be the 1st line treatment option for splenic marginal zone lymphoma (SMZL) but recent studies have shown that rituximab is equally effective if not better treatment option in terms of overall survival. Splenectomy is still performed but mainly in patients with splenomegaly without lymphadenopathy having low surgical risk or in those who are refractory to rituximab therapy.