Non‐Hodgkin Lymphomas

Abstract Non‐Hodgkin lymphomas (NHLs) are malignant neoplasms of lymphoid cells, the predominant cells of the immune system. This term encompasses lymphocytes and their precursor as well as their progeny cells and natural killer cells. The defining characteristics of NHLs are their gene and microribonucleic acid (miRNA) expression patterns, which differ for each lymphoma subtype and also from those of closely related normal cell types. This is a consequence of a broad range of genetic changes – including gross changes at chromosomal level, namely translocations, whole or partial chromosome losses and other, smaller changes in individual genes ranging from point mutations to deletions that result in modifications of the molecular pathways of cells that cause corresponding modifications in cell behaviour. The genetic changes that give rise directly to NHLs are induced by physical, chemical or biological environmental agents (rarely, genetic changes that predispose to lymphomas may be inherited or present from birth) or the presence of viral sequences capable of modifying normal gene expression pattern and/or molecular pathways in the relevant cell type. At the clinical level, the behaviour of malignant lymphomas varies from indolent to aggressive. Lymphomas may be observed, treated with chemotherapy or with various combinations of chemotherapy, radiation and occasionally surgery (e.g. splenectomy). Key Concepts: NHLs are malignant neoplasms that arise from lymphoid cells, the predominant cells of the immune system, which include lymphocytes and their precursor and progeny cells. The immediate cause of lymphomas is genetic change, often chromosomal aberrations such as translocations, but this may be predisposed to by infections, particularly those that influence immunoregulation. Clinical distinctions such as nodal and extranodal lymphomas or bone marrow involvement, once the primary means of identifying diseases, do not have taxonomic significance (i.e. they are not, in themselves, indicators of a different disease). Mature lymphoid cells express an antigen‐binding receptor that is the external starting point of a major signalling pathway extending to the cell nucleus that is critical to lymphoid cell proliferation; mutations in this signalling pathway may simulate tonic expression of the TCR or BCR, even if the latter are normal, therefore, giving rise to inappropriate cell proliferation in the absence of antigen. The requirement of the adaptive immune system for antibodies to be able to bind tightly to antigen, which is achieved by selection of the antibody with the ‘best fit’ to antigen in the germinal follicle through a process of somatic mutation within the antibody variable region (see immune system and also class switching), a process mediated by activation‐induced cytidine deaminase, can result in significant structural rearrangements within the antibody molecule, including double‐strand breaks in the DNA. These processes, which have been shown to increase the risk of developing chromosomal translocations in mice, are probably relevant to the genesis of major cytogenetic changes in human lymphoid cells, some of which may be pertinent to lymphoma development. Some chronic infections and inflammatory processes cause activation of lymphoid cells, and predisposition to lymphoma development. Inherited (e.g. XLP) and acquired immunodeficiencies (e.g. HIV) may increase the risk of lymphoma development by modifying regulation of the immune system. Understanding the molecular mechanisms of lymphomagenesis as well as the molecular changes associated with lymphocyte differentiation can lead to targeted approaches to therapy, that is, the development of molecules which bind with high specificity to identified molecular targets, and either modify their actions or enable the introduction of a high local concentration of toxin or radionuclide, in either case producing a potentially therapeutic effect which is likely to be more specific and less toxic than conventional chemotherapy. When chronic infection leads to lymphoma, treatment of the underlying disease may induce complete remission and sometimes cure. In general, the more aggressive (rapidly progressive) lymphomas respond well to intensive therapy, and a proportion of such cases can be cured although recent research has suggested that some indolent lymphomas are also potentially curable by drugs that alter the microenvironment they require for survival.