Marginal zone lymphoma

Marginal zone lymphomas, also known as marginal zone B-cell lymphomas, are a heterogeneous group of lymphomas that derive from the malignant transformation of marginal zone B-cells. Marginal zone B cells are innate lymphoid cells that normally function by rapidly mounting IgM antibody immune responses to antigens such as those presented by infectious agents and damaged tissues. They are lymphocytes of the B-cell line that originate and mature in secondary lymphoid follicles and then move to the marginal zones of mucosa-associated lymphoid tissue, the spleen, or lymph nodes. Mucosa-associated lymphoid tissue is a diffuse system of small concentrations of lymphoid tissue found in various submucosal membrane sites of the body such as the gastrointestinal tract, mouth, nasal cavity, pharynx, thyroid gland, breast, lung, salivary glands, eye, skin and the human spleen.
In 2016, the World Health Organization classified MZLs into three different types. Extranodal marginal zone lymphomas are MZLs that develop in extranodal tissues. Most EMZLs develop in MALT and are often termed extranodal MZL of mucosa-associated lymphoid tissue or, more simply, MALT lymphomas. Splenic marginal zone lymphomas are MZLs that initially are confined to the spleen, bone marrow, and blood. Nodal marginal zone lymphomas are MZLs initially confined to lymph nodes, bone marrow, and blood. While all of these MZL involve malignant B-cells, they differ not only in the tissues they involve but also in their pathophysiology, clinical presentations, prognoses, and treatments.
MZLs represent 5–17% of all Non-Hodgkin lymphomas with the extranodal, splenic, and nodal forms accounting for 50–70%, ~20%, and ~10% of all MZLs. The three MZL subtypes occur more often in older people and are indolent diseases that may, in people without symptoms, be initially treated by a watchful waiting strategy. However, NMZL carries a somewhat worse long term outcome than the other subtypes and any of the MZL subtypes may progress in a low percentage of cases to a more aggressive lymphoma, particularly diffuse large B-cell lymphoma. One of the most distinctive features of MZL is that many cases are associated with the persistent simulation of the immune system by the chronic inflammation that accompanies infections or autoimmune diseases. MZL cases associated with certain infectious pathogens can be cured by treatment directed at the pathogens causing or associated with these infections.

Extranodal marginal zone lymphoma

Extranodal marginal zone lymphomas are a form of MZL in which malignant marginal zone B-cells initially infiltrate MALT tissues of the stomach or, less frequently, the esophagus, small intestine, large intestine, rectum, conjunctiva of the eye, nasal passages, pharynx, lung bronchi, vulva, vagina, skin, breast, thymus gland, meninges that envelop the brain and spinal cord, or other organs. These EMZLs are classified into subtypes based on the organ involved. For example, EMZL of the stomach is termed primary gastric EMZL. Regardless of subtype, these EMZLs share similar pathophysiological and histopathological. However, the subtypes differ in presentation, progression, severity, treatment, and instigating factors. The following two sections describe the common pathophysiologic and histopathologic features found in all EMZL subtypes. Features specific to each EMZL subtype follow these two sections.

Pathophysiology

Numerous factors appear to be involved in the development of EMZL. In a small number of cases where there is a family history of a blood cancer particularly leukemia, or a number of autoimmune diseases such as Sjögren syndrome and lupus erythematosus, there is seen to be an increased frequency. Inherited genetic, shared environmental, and other as yet unidentified factors may underlie these increased risks of developing an EMZL. Another key factor in the initiation of many EMZL cases is chronic inflammation caused by a chronic infection or autoimmune reaction. The chronic inflammation stimulates B-cells to rearrange their immunoglobulin heavy chain locus so that they encode B-cell receptors that recognize unnatural antigens presented by the injured issues and/or infectious agents that underlie the inflammation. This rearrangement results in the B-cells responding to the abnormal antigens by taking on features of marginal B-cells and proliferating excessively. In consequence, these B cells progressively acquire in a step-wise fashion chromosome abnormalities, gene mutations, and/or dis-regulated genes that contribute to their becoming malignant. The acquired genomic abnormalities found in EMZL along with the frequency of occurrence in specific EMZL subtypes include the following.

Chromosome translocations: 1) A translocation of the long arm of chromosome 11 at position 21 with the q arm of chromosome 18 at position 21 occurs in 24% of gastric, 38% of lung, and rarely other EMZL subtypes. This translocation places a part of the API2 gene with a part of the MALT1 gene to create a fusion gene that encodes an Api2-Malt1 fusion protein. This chimeric protein promotes the continuous activation of a transcription factor, NF-κB. NF-κB controls the expression of various genes which increase the survival, cytokine production, and other potentially malignant behaviors of cells. 2) A t A t A t Three translocations, t, t, t, and t, occur in rare cases of EMZL but their effects on promoting malignancy are unknown.
Gene inactivations and mutations: 1) Inactivation or the TNFAIP3 gene due to its deletion on chromosome 6 about position 23 Gain-of-function mutations in the MYD88 gene occur in ~5% of ocular adnexa EMZL cases. The product of this gene, myeloid differentiation primary response 88, continuously activates NF-κB as well as the STAT3 and AP1 transcription factors. 3) Inactivating mutations in the NOTCH1 and NOTCH2 genes occur in EMZL. The products of these genes are cell surface receptor proteins which when bound to their activating ligands move to the cell nucleus and contribute to the activation of genes that control the development, proliferation, survival, and migration of B cells.

Many EMZL subtypes are associated with infectious agents or autoimmune diseases that may contribute to their malignant development. The following Table reports on these EMZL subtypes; the tissues they involve; the infectious agents/autoimmune diseases that may underlie the development of the EMZL subtypes; the strength of evidence linking these infectious agents/autoimmune diseases to their malignancy; the incidence of cases with the EMZL subtype associated with the infectious agent/autoimmune disease; and some of the chimeric genes expressed by the neoplastic B-cells of the EMZL subtype.

Subtype	Tissue involved	Infectious agent or autoimmune diseasen	Strength of evidence	Incidence	Chimeric genes expressed
Primary gastric EMZL	stomach	Helicobacter pylori	confirmed	~80%	BIRC3-MALT1, IGH-FOXP1, IGH-BCL-10, and IGH-MALT1
Primary gastric EMZL	stomach	Helicobacter heilmannii sensu lato	likely	<1%	similar to the antibiotics used for Helicobacter pylori
Primary salivary gland EMZL	salivary and lacrimal glands	Sjögren syndrome	confirmed	~4.3%	IGH-MALT1, BIRC3-MALT1, and IGH-BCL-10
Primary thyroid EMZL	thyroid gland	Hashimoto's thyroiditis	confirmed	~0.5%	ICH-FOXP1 and BIRC3-MALLT1
Primary ocular adnexa EMZL	ocular adenexa	Chlamydia psittaci	suggestive	10–50%	IGH-FOXP1, and BIRC3-MALT1
Primary cutaneous EMZL	skin	Borrelia burgdorferi	suggestive	variable	IGH-FOXP1, IGH-MALT1, and BIRC3-MALT1
Primary small intestinal EMZL	small intestine	Campylobacter jejuni	low	variable	BIRC3-MALT1 and IGH-BCL10
Primary pulmonary EMZL	lung	Achromobacter xylosoxidans	low	<50%	BIRC3-MALT1, IGH-BCL10, and IGH-MALT1

Histopathology

The histopathologic examination of EMZL lesions typically reveals a vaguely nodular or diffuse pattern of cells. The malignant cells in these lesions have, in varying proportions, the morphology of small-to-medium-sized lymphocytes, centrocyte-like B cells, centroblast-like B cells, monocyte-like B cells, plasma cell-like B cells, and/or large B cells. When the large B cells form prominent sheets that are clearly separated from cells with the other, low-grade malignant morphologies, the disease may be transforming to the far more aggressive malignancy, diffuse large B-cell lymphoma. This transformation occurs in ~18% of patients at a median of 4–5 years after the original diagnosis of EMZL. Immunophenotyping or the neoplastic large B cells in these lesions shows that they express CD20 but not CD3 surface membrane B cell marker proteins. The cells almost always express BCL2 and may express MNDA, CD23 and CD5 marker proteins but do not express the cyclin D1 marker protein., the T-cell marker, CD10, or BCL6.

Subtypes, diagnosis, treatment, and prognosis

There are various EMZL subtypes based on the organs they involve. Almost all of these subtypes occur in the mucosa-associated lymphoid tissue of the affected organ and are often termed MALT lymphomas of the affected organ. However, these lymphomas are also termed primary EMZL of the affected organ. While both terms are used here for these subtypes, the primary EMZL is preferred to indicate that the EMZL subtype initially developed in and may remain limited to the indicated tissue. However, approximately 30% of cases disseminate to other sites, predominantly lymph nodes and in rare cases the bone marrow. The malignant B-cells in these subtypes may also circulate in the blood but this is very uncommon. Regardless of the subtype of EMZL or its dissemination to other tissues, the prognosis for these lymphomas is good with 5 year overall survivals generally ranging between 86% and 95%.