br Marginal zone lymphoma Marginal zone lymphoma MZL
Marginal zone lymphoma Marginal zone lymphoma (MZL) comprises three lymphoma entities that arise from the marginal zone surrounding the germinal center: extranodal MZL or mucosa-associated lymphoid tissue (MALT), splenic MZL, and nodal MZL. Deep sequencing of nodal MZL patients found that 5/35 (14%) cases had a mutation in the adhesion receptor ADGRV1 (also known as GPR98) and the cadherin receptors CELSR1, CELSR2 and CELSR3 were each mutated in 2/35 (6%) cases . In addition to mutation, t(X;14) translocations causing upregulation of purinergic receptor GPR34 were observed in 2/61 (3%) cases of MALT, 1/43 (2%) cases of nodal MZL and 1/19 (5%) cases of extranodal DLBCL . When compared to healthy B and T cells, GPR34 mRNA faah inhibitor was significantly upregulated in MALT, nodal and splenic MZL and increased gene expression of GPR34 in was correlated with high expression of the orphan receptor GPR82. Overexpression of GPR34 in cell culture experiments resulted in increased cell proliferation and increased phosphorylation of the kinases ERK and PKC and cAMP response element-binding protein (CREB) . Other GPCRs that had elevated expression in MZL include the S1P family receptors S1PR1 and S1PR3  and the gastrin/cholecystokinin receptor CCKBR . A fraction of MALT patients were immunopositive for the somatostatin receptors SSTR1 (1/55, 2%), SSTR2 (15/55, 27%), SSTR3 (20/55, 36%), SSTR4 (10/55, 18%) and SSTR5 (28/55, 50%) and there was a significant association between SSTR5 negativity and poor patient outcome . SSTR-receptor scintigraphy was demonstrated to be useful for staging and follow-up in MALT  although there is disagreement concerning whether gastric tumors have higher SSTR3, SSTR4 and SSTR5 than extragastric tumors , . Chemokine receptor expression in MZL subtypes is shown in Table 1. CXCR3 is strongly expressed on the surface of the majority of MZLs and was identified via IHC in 14/14 (100%) patients with splenic MZL, 15/16 (94%) patients with extranodal MZL  and 5/5 (100%) cases of epidermotropic MZL . One study found that only 13% of cutaneous MZLs were CXCR3-positive compared to 85% of other extranodal MZLs implying that CXCR3-negative patients comprise a unique subtype of MZL . CXCR3 is a predictor of non-responsiveness for H. pylori eradication therapy implying that CXCR3 helps protect tumors from this treatment . MALT lymphoma cells are known to express CXCR3 and migrate to the CXCR3 ligand CXCL9 (also known as MIG)  and both high- and low-grade MALT originating from the thyroid and stomach had high CXCR3 and low CCR4 cell surface expression . However, CCR4 protein expression itself was significantly more highly expressed in trisomy 3-positive compared to trisomy 3-negative MALT and correlated with advanced disease stage and poor prognosis . Although CXCR4 and CXCR5 are generally expressed in MZL , , , , flow cytometry of splenic MZL tissues with minimal lymphadenopathy had significantly reduced expression of CXCR4, CXCR5 and CCR7 compared to normal B cells and B cell neoplasm with nodular dissemination such as CLL, MCL and FL . Exome sequencing found 2/35 (6%) cases of MZL had a mutation in CXCR4  and the CXCR4WHIM mutation was found in 1/20 (5%) MZL patients . A significant correlation has been observed between CXCR4 expression and bone marrow involvement and loss of CXCR4 expression combined with upregulation of CXCR7 has been suggested to correlate with MALT progression to DLBCL . Other chemokine receptors that are expressed in MZL include CCR8, CCR9, CXCR6 and CXCR7, which were immunopositive in the majority of gastric MALT lymphomas . Two independent studies found that 84–88% of MALT cases stained positive for CCR6, which is known to play a role in migration and B cell maturation , . In addition, CCR1 protein expression was found to be subtype-specific as 3/6 (50%) nodal MZL cases expressed CCR1 compared to only 1/21 (5%) extranodal MZL and 0/5 splenic MZL cases .