The B Lymphocyte Predominance: Marginal Zone Lymphoma

Marginal zone lymphoma (MZL) denominates a category of indolent B lymphocytic lymphomas engendered from the marginal zone of lymphoid follicles. Marginal zone lymphomas comprise of an estimated (8%) of non-Hodgkin’s lymphomas with a median age of disease emergence at 60 years and a slight female preponderance. Marginal zone lymphomas display identical morphological and immune phenotypic features across the subcategories. The world health organization (WHO) designates marginal zone lymphoma into three distinct subtypes as extra nodal marginal zone lymphoma (mucosa associated lymphoid tissue MALT lymphoma), nodal marginal zone lymphoma and splenic marginal zone lymphoma. Primary nodal marginal zone lymphoma remains an exceptional entity and necessitates a demarcation from secondary nodal marginal zone lymphoma on account of metastasis from extra nodal or splenic marginal zone lymphoma. Nodal marginal zone lymphoma constitutes an estimated 2.4% and splenic marginal zone lymphoma around 0.7% of the B lymphocytic lymphomas.


Introduction Nodal marginal zone lymphoma
The exceptional neoplasm constitutes an estimated 2% of the B cell lymphomas with a majority of the subjects presenting with clinical stage III or IV. The indolent lymphoma may demonstrate a clinical course recapitulating follicular lymphoma with divergent clinical manifestations. Nodal marginal zone lymphoma may characteristically be engendered from the lymph node follicles. It may partially recapitulate morphological, immune phenotypic and genetic manifestations of an extra nodal rather than a splenic marginal zone lymphoma [1][2][3]. Nodal marginal zone lymphoma as an infrequent disorder may account for approximately 10% of marginal zone lymphomas. The contemporary classification of world health organization (WHO) defines the nodal variant as a primary nodal B cell neoplasm morphologically identical to a lymph node with attributes of a marginal zone lymphoma of the extra-nodal or splenic subtype in the absence of splenic or extranodal disease. In contrast to splenic and extra-nodal marginal zone lymphoma, the nodal variant depicts an inferior outcome [2].

Clinico-pathological elucidation
A peripheral lymph node enlargement situated in the head and neck region may be the preliminary presentation. Bone marrow may be implicated in an estimated 30%-60% individuals. Serum chemistries may demonstrate enhanced levels of β2 microglobulin and lactate dehydrogenase (LDH) in approximately one third (34%) of subjects. The serum M component may be detectable in roughly 10% instances though the percentage may vary. Clinical features, histopathology and disease outcome of the neoplasm may be insufficiently elucidated as nodal marginal zone lymphoma has been described as a separate entity by the world health organization since 2008 [3,4].
Nodal marginal zone lymphoma may be accompanied by autoimmune disorders such as rheumatoid arthritis, vitiligo, systemic lupus erythromatosus, chronic thyroiditis and Sjogren's syndrome with an amplification of infection with hepatitis C virus (HCV). Nodal marginal zone lymphoma may be cogitated as a disorder of obscure pathogenesis [1].
Nodal marginal zone lymphoma may recapitulate follicular lymphoma although the disease may relapse frequently with increasingly aggressive reoccurrences.

Morphological characteristics
Nodal marginal zone lymphoma may typically depict a parafollicular, peri-follicular and inter-follicular tumour configuration.

Immune phenotypic markers
Nodal marginal zone lymphoma may be devoid of a characteristic immune phenotype. Thus, typical immune phenotype or cytogenetic features elucidating nodal marginal zone lymphoma may be challenging to discern. B lymphocytic markers such as CD19+, CD20+, CD79a+ and PAX5+ may be elucidated though nodal marginal zone lymphoma may be non-reactive for CD5-, CD10-and CD23-. Concurrent immunoglobulin M (Ig M) and immunoglobulin D (IgD) may be typically exemplified with splenic marginal zone lymphoma, although the feature may be ambiguous and infrequent with nodal marginal zone lymphoma.
Majority of nodal marginal zone lymphomas may demonstrate frequent somatic mutations of the immunoglobulin heavy chain variable (IGHV) genes, particularly the IGHV3 and IGHV5 subtypes. Trisomy of chromosome 3 and 18 may be enunciated. The diagnosis of nodal marginal zone lymphoma may be one

Molecular aspects
Comparative genomic hybridization (CGH) of nodal marginal zone lymphoma may recognize reoccurring genomic gains of chromosomes 3,12 and 18. However, singular genes concurrent with onco-genesis may not be identified. Repetitive and frequent chromosomal translocations of associated lymphoid neoplasm may be lacking in nodal marginal zone lymphoma. A whole exome sequencing (WES) analysis may delineate oncogenic           Table 1 Immune phenotypic and cytogenetic attributes of Nodal marginal zone lymphoma [1].
Somatic mutations of NOTCH2, KLF2, MLL2, TP53. Frequent IGHV1-02.    For treated patients at the end of treatment, every 4-6 weeks for first 3 months then every 6 months. immunoglobulin D (IgD). Additionally, BRAF V600 E mutations may be enunciated in hairy cell leukemia, chronic lymphocytic leukaemia, pro-lymphocytic leukaemia, classic Hodgkin's lymphoma and splenic marginal zone lymphoma. The BRAF molecule encodes for a serine /threonine kinase which may be generally activated by a V600E somatic point mutation. The aforementioned aberration remains a frequent genetic rearrangement in malignant transformation. The particular kinase-activating mutation provides a therapeutic target for BRAF kinase inhibitors [5]. Nodal marginal zone lymphoma may depict repetitive genetic lesions associated with the development of marginal zone B cells. Genes such as NOTCH1, SPEN and DTX1 of the NOTCH signalling pathway may be critical for normal differentiation of the marginal zone. Recurrent mutation of the NF₭B pathway may be elucidated with nodal marginal zone lymphoma which may also impair genes such as TNFAIP3 and BCL10. Pharmacologic disruption of the NOTCH or NF₭B signalling pathway may be appurtenant in nodal and splenic marginal zone lymphoma. Reoccurring mutations in the genes encoding for chromatin remodelling and transcriptional regulation may be discerned. The histone methyl transferase KMT2D, the acetyl transferases CREBBP and TBL1XR1 a critical constituent of the N-Cor co-repressor complex may depict genetic rearrangements [1]. The aforementioned mutations of epigenetic regulators may appear in an estimated 40% of nodal marginal zone lymphomas and may make therapeutic opportunities with agents such as histone deacetylase (HDAC) inhibitors accessible. Genomic aberrations of BRAF, TET2, EZH2, KMT2D, CREBBP, TNFRSF14 and FAS genes may be found singularly in nodal marginal zone lymphoma. FAS encodes a receptor of the TNF family which may prominently impact extra cellular apoptotic signaling. Genetic mutations, particularly in the protein death domain may eradicate the genomic objective in order to imbue a resistance to the cell for apoptosis. FAS may be frequently mutated in autoimmune lympho-proliferative syndrome, adult T cell lymphoma and diffuse B cell lymphomas (DLBCL). Appropriate categorization of TNFAIP3, CREBBP, EZH2 and TNFRSF14 may assist in developing an improvised molecular classification of nodal marginal zone lymphoma [7,8].

Investigative assay
Monocytoid B cells (MBCs) are a subset of B cells that may be recognized in several reactive and tumourous lymph node conditions, including toxoplasma lymphadenitis, infectious mononucleosis and Hodgkin's lymphoma. Although this is a commonly observed cell population, which has even given its name to a type of lymphoma, MBC lymphoma, scarcely any information is available about the function and characteristics of this cell type. Specific markers of MBC are still lacking, and this makes it difficult to analyze their relationship with other B cell subpopulations and to confirm the existence of tumours derived from this cell subpopulation. Reactive lymphocytes predominate in effusions from non-haematopoietic malignancies and benign conditions, while a significant proportion of fluids from patients

Therapeutic strategies
As nodal marginal zone lymphoma is an indolent disorder an active surveillance may be acceptable until constitutional symptoms emerge. The optimal therapeutic applications of nodal marginal zone lymphoma remain undefined though options such as radiotherapy, chemotherapy and/or immune therapy may be available. European Society of Medical Oncology advocates the adoption of treatment modalities applicable for alleviating follicular lymphoma. Localized radiotherapy may be beneficial in appropriately curtailing the tumour in individuals with restricted disease [9,10]. A proportion of 24 Gy may be suitable for targeting focal and implicated disease configurations. A minimal quantification (4 Gy) of radiation therapy may prove to be advantageous for palliative recommendations in stages of dissemination and clinical disease advancement along with the optimal employment of immunotherapy [10,11].
Nodal marginal zone lymphoma may be managed with a combination of rituximab with cyclophosphamide, doxorubicine, vincristine and prednisone (RCHOP) or bendamustine combined with rituximab. Bendamustine with concomitant rituximab may depict identical outcomes as achieved with R CHOP, particularly the progression free survival (PFS), though bendamustinerituximab may depict a reduced toxicity. The initiating therapy may be with antibody drug conjugates such as rituximab, immune modulatory agents such as lenalidomide along with rituximab or the employment of ibrutinib tiuxetan for clinical stage 2B [11,12]. Elderly patients may benefit from therapeutic induction with chlorambucil or cyclophosphamide in combination with rituximab or singular application of chlorambucil or cyclophosphamide. Subsequent therapy as a second line option may frequently be the employment of concomitant chemo-immunotherapy or disease alleviation with ibrutumomab, tiuxetan. Ibrutinib may be employed for managing relapsed nodal marginal zone lymphoma.
As the nodal marginal zone lymphoma conjectures as an elusive entity, acceptable evidence to engender optimal therapeutic regimens remain undefined [12,13].

Splenic marginal zone lymphoma
A frequent lymphoma of the spleen may be denominated by the splenic marginal zone lymphoma at an estimated < 2% of comprehensive lymphoid neoplasm. Median age of disease emergence is roughly 65 years with equivalent gender prevalence. Splenic marginal zone lymphoma represents an indolent, slowly progressive disorder. The median overall survival (OS) may exceed a duration of 10 years, although one third instances delineate an aggressive disease with a consequent decline in the overall survival (OS). In about an estimated 5% individuals demonstrate a malignant transformation into a "large B cell lymphoma" [1,2].

Clinical elucidation
Majority of the subjects may be asymptomatic with an accidental discernment of anaemia and thrombocytopenia in the complete blood counts. A clinical emergence of splenomegaly may be associated with anaemia, autoimmune thrombocytopenia and varying quantification of villous lymphocytes in the peripheral blood. With advanced, progressive disease. systemic symptoms may appear on account of splenomegaly such as abdominal discomfort, pain and declining blood counts with pancytopenia [1,3]. For appropriate interpretation of splenic marginal zone lymphoma, a correlation of clinical features, laboratory parameters, histological manifestations and radiological aspects may be necessitated, as with associated marginal zone lymphomas.
The etiology of splenic marginal zone lymphoma remains obscure though chronic antigenic stimulation may provide a trigger for the initiation of disease. Splenic marginal zone lymphoma may be frequent with the carriers of hepatitis C virus (HCV) carriers and eradication of viral infection may induce a remission of the lymphoma. The contingency may be elucidated in southern Italy and regions of North America [13,14].

Histological elucidation
Miniature malignant lymphoid cells may constitute the hall mark of the neoplasm. Marginal zone of the white pulp may engender the lymphoma which secondarily invades the hilar lymph nodes of the spleen. The bone marrow infiltrate may elucidate a characteristic sinusoidal configuration. The liver may appear as an adjunctive and frequent site of tumor secondary ingress. Instances of leukemic infiltration and a lack of peripheral lymph node enlargement may be cogitated [3,4].

Immune phenotype
The

Investigative assay
A comprehensive medical history with a general physical examination, complete blood counts and serum chemistries such as liver function tests, renal function tests, lactate dehydrogenase (LDH) and β2 micro-globulin may be ascertained. An estimated 10%-15% of subjects may demonstrate the emergence of autoimmune diseases as delineated with appropriate evaluation. Attributes computing the prognostic signs may incorporate anaemia, thrombocytopenia, extra hilar lymph node enlargement with an elevated serum lactate dehydrogenase (LDH) and reduced serum albumin values, which may applicable for risk stratification of patients. Tumour invasion extending to non haematopoietic viscera may display an inferior outcome. A splenectomy may no longer be the preferred therapeutic option for managing splenic marginal zone lymphoma as the characteristics diagnostic aspects may be discerned on bone marrow and flow cytometric analysis of the peripheral blood [1][2][3][4].

Molecular aspects
Splenic marginal zone lymphoma may lack the elucidation of specific genetic markers. Trisomy of chromosomes 3 and 18 with a deletion of 7q31.31-q32.3 may be a frequent genetic aberration and characteristic of a splenic marginal zone lymphoma. Somatic mutations of KLF2 gene with anomalies of the NOTCH and NF₭B pathway may be concurrent and frequent eventualities. Associated chromosomal aberrations may not be universally discernible. Somatic mutations of the immunoglobulin heavy chain variable (IGHV) gene may be discerned in an estimated half (50%) of the individuals with concomitant enunciation of IGHV1-2 and IGHV3-23(1). An estimated one third (34%) instances of splenic marginal zone lymphoma may present the IGHV1-02 gene and a majority (90%) of the subjects may incriminate the allele O4 polymorphic variant (79). The aforementioned findings may implicate an antigenic stimulation and/or a genesis from the progenitor cells sensitive to specific antigenic triggers due to the incitement of particular VH domains [5,6].

Management of Therapeutic strategies
The management of splenic marginal zone lymphoma may be devoid of specific recommendations. As the neoplasm is indolent, a policy of simple observation may be appropriate. A preliminary therapeutic intervention for patients with mild splenomegaly and a lack of systemic symptoms may not prove to be advantageous. Solitary administration of rituximab or with the addition of ibrutinib may be adopted [14,15] (Tables 1-6).
However, subjects infected by hepatitis C virus (HCV) may adopt and benefit from an antecedent antiviral therapy. A combination with or singular interferon administration (in the absence of hepatitis C virus infection) may be opted for. Attributes which indicate commencement of therapeutic intervention as per the society of European medical oncology (ESMO) may incorporate i) progressive splenomegaly, ii) progressive decline in the blood cell counts or pancytopenia, iii) declining haemoglobin values of below <10 grams/decilitre, iv) platelet count beneath <80,000 /µLitre and v) an absolute neutrophil count below <1000 cells/ µLitre [1]. Splenectomy as a conventional therapeutic option may alleviate the splenomegaly with concomitant constitutional symptoms and augment the blood cell counts in a majority. A median progression free survival (PFS) of 5 years may be exemplified. However, surgical extermination of the spleen may not impact the disease incrimination within the bone marrow or peripheral blood. Chemotherapy, immunotherapy or a minimal dose of radiotherapy to the spleen may be employed for subject's ineligible or unwilling for a surgical eradication of the spleen. Chemotherapeutic regimens adopting alkylating agents such as chlorambucil or cyclophosphamide may be administered. Singular agents such as fludarabine may be minimally beneficial.
Solitary rituximab or as a combination therapy may procure an enhanced overall survival (OS) and complete response rate (CRR) [15,16].

Conclusion and Follow up
Asymptomatic patients of splenic or nodal marginal zone lymphoma may be monitored every 6 months. Procedural investigations for treated subjects may be as frequent as in 4-6 weeks during the first three months. An observation for transformation into a high-grade malignant lymphoma may be a pre-requisite for the variants of marginal zone lymphoma.