Extranodal Marginal Zone Lymphoma: Pathogenesis, Diagnosis and Treatment

Abstract

Extranodal Marginal Zone Lymphoma (EMZL lymphoma) is an indolent B-cell lymphoma with a median age at diagnosis of about 60 years. It accounts for 7-8% of all B-cell lymphomas. It can occur in various extranodal sites, including stomach, lung, ocular adnexa, and skin; furthermore, the disseminated disease can be found in 25-50% of cases. Several infectious agents, such as Helicobacter pylori (H. Pylori) in the case of gastric Mucosa Associated Lymphoid Tissue (MALT) Lymphoma, can drive the pathogenesis of this cancer, through the autoantigenic stimulation of T cells, but there may also be other factors participating such autoimmune diseases. Initial staging should include total body computed tomography, bone marrow aspirate, and endoscopic investigation if indicated. Fluorescence in situ hybridization (FISH), should be performed to detect the presence of specific chromosomal translocations involving the MALT1 and BCL10 genes, which leads to the activation of the NF-κB signaling pathway. Depending on the location and dissemination of the disease, different therapeutic choices may include targeted therapy against the etiopathogenetic agent, radiotherapy, immunochemotherapy, and biological drugs. The purpose of this review is to illustrate the complex biology and the diagnosis of this disease and to better define new treatment strategies.

Keywords: BALT; MALT; OAL; diagnosis; immunotherapy; marginal zone lymphoma; non-Hodgkin lymphoma; prognosis; targeted-therapy; treatment.

Figure 1

Etiopathogenesis of Extranodal Marginal Zone Lymphoma. Chronic antigen stimulation is given by associated infections (H. pylori, C. Psittaci, etc.) and/or autoimmune diseases and sustains inflammation. T-Cell activation and Neutrophils chemotaxis are enhanced, producing cytokines and Reactive oxygen species (ROS), which are responsible for peripheral B-Lymphocytes activation and proliferation. Inflammation causes the upregulation of NF-kB pathway, through Toll-like receptors (TLR), B cell receptor (BCR), B-cell activating factor (BAFF), and the exposure of DNA to the damaging effects of ROS. Mutations and Genomic aberrations can occur in this context, promoting tumorigenesis and transformation into Extranodal Marginal Zone Lymphoma (EMZL) cells. Acquired mutations can occur, such as deletions of p53 and or p16, leading to DLBCL transformation. CAG-A, Cytotoxin-associated antigen A; BIRC3/MALT1, t(11;18); IGH-MALT1, t(14;18); IGH-BCL10, t(1;14); IGH-FOXP1, t(3;14); DLBCL, Diffuse Large B-Cell Mutations.

Figure 2

Treatment algorithm for stage IE-II gastric-MALT Lymphoma. H. pylori, Helicobacter pylori; PPi, Proton pump inhibitors; EGDS, Esophagogastroduodenoscopy; IFRT, Involved field radiotherapy.

Figure 3

Therapeutic algorithm for lung EZML. R-CHOP, Rituximab, Cyclophosphamide, Vincristine, Adriblastine, Prednisone; R-CVP, Rituximab, Cyclophosphamide, Vincristine, Prednisone.

Figure 4

Therapeutic algorithm for ocular adnexa EZML. C. psittaci, Chlamidophila psittaci; R-CHOP, Rituximab, Cyclophosphamide, Vincristine, Adriblastine, Prednisone; R-CVP, Rituximab, Cyclophosphamide, Vincristine, Prednisone.